Crystalline form of 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-D3)pyridazine-3-carboxamide

Abstract

The present disclosure relates to a number of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 ) Crystalline forms of pyridazine-3-carboxamide: Crystalline form L, Crystalline form M, Crystalline form N, Crystalline form O, Crystalline form P, Crystalline form Q, Crystalline form R, Crystalline form S, Crystalline form T, Crystalline form U, Crystalline form V, Crystalline form W, Crystalline form X, Crystalline form Y, Crystalline form Z, Crystalline form AA, Crystalline form AB, Crystalline form AC, Crystalline form AD, Crystalline form AE, Crystalline form AF, and Crystalline form AG are described together with the data characteristics of each of these crystal forms.

Description

[Technical field]

[0001] The present invention generally relates to crystalline forms of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide. The present invention also generally relates to pharmaceutical compositions containing the crystalline forms, as well as methods for obtaining the crystalline forms. [Background technology]

[0002] The compound, 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, has the formula (I): [ka] Compound (I) has the structure: embedded image and is referred to herein as "Compound (I)". Compound (I) is disclosed in commonly assigned U.S. Patent RE47,929 E. U.S. Patent RE47,929 E also discloses a method of treatment using Compound (I). Compound (I) is also known as ducevacitinib.

[0003] Compound (I) is a Tyk2 inhibitor currently in clinical trials for the treatment of autoimmune and autoinflammatory diseases (e.g., psoriasis, psoriatic arthritis, lupus, lupus nephritis, Sjogren's syndrome, inflammatory bowel disease, Crohn's disease, and ankylosing spondylitis).

[0004] In the synthesis of compounds intended for pharmaceutical use, the compounds need to be isolated and purified at the stage where the synthesis process is completed and before further processing to obtain the compound in a pharmaceutical formulation. Successive isolation and purification steps, which can be performed simultaneously or independently, can provide the compound as a purified solid. Ideally, there is minimal loss of yield during isolation of the compound from other components of the reaction mixture and / or purification to remove impurities from the isolated compound sample.

[0005] It is desirable to provide solid forms of the compounds that can be reproducibly produced from the isolation and / or purification steps.

[0006] It is desirable to isolate a compound that is a solid that is physically and chemically stable during storage under different conditions of temperature and humidity. Additionally, it is desirable to provide a solid compound that is amenable to further processing (e.g., a crystalline form that can be converted to other solid forms, such as an amorphous solid or other crystalline forms).

[0007] Furthermore, the physicochemical properties of a compound can be altered by using different crystal forms. In some cases, the physicochemical properties of a compound can be altered by the formation of a co-crystal. Co-crystallization can also be used to isolate or purify a compound during preparation.

[0008] As described herein, crystalline forms of Compound (I) are surprisingly amenable to further processing and conversion to other solid forms.The present invention is directed to these and other important aspects. Summary of the Invention

[0009] The present invention provides crystalline forms of Compound (I), namely, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S, Form T, Form U, Form V, Form W, Form X, Form Y, Form Z, Form AA, Form AB, Form AC, Form AD, Form AE, Form AF, and Form AG. It is understood that the names used herein to characterize a particular form (e.g., Form L, Form M, etc.) should not be limited with respect to any other substance having similar or identical physical and chemical properties, but rather, the names are merely identifiers that should be interpreted according to the information regarding the properties also provided herein. [Brief description of the drawings]

[0010] [Figure 1]FIG. 1 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form L of compound (I). [Diagram 2] FIG. 2 shows a graph (top) of thermogravimetric analysis (TGA) of crystalline form L of compound (I) and a graph (bottom) of differential scanning calorimetry (DSC) of crystalline form L of compound (I). [Diagram 3] FIG. 3 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form M of compound (I). [Figure 4] FIG. 4 shows a graph of thermogravimetric analysis (TGA) of crystalline Form M of Compound (I) (top) and a graph of differential scanning calorimetry (DSC) of crystalline Form M of Compound (I) (bottom). [Diagram 5] FIG. 5 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline Form N of Compound (I). [Figure 6] FIG. 6 shows a graph of thermogravimetric analysis (TGA) of crystalline Form N of Compound (I) (top) and a graph of differential scanning calorimetry (DSC) of crystalline Form N of Compound (I) (bottom). [Figure 7] FIG. 7 shows the powder X-ray diffraction pattern (CuKα, measured at room temperature) of the observed crystalline form O of compound (I). [Figure 8] FIG. 8 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form P of compound (I). [Figure 9] FIG. 9 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form Q of compound (I). [Figure 10] FIG. 10 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form R of compound (I). [Figure 11] FIG. 11 shows a graph of thermogravimetric analysis (TGA) of crystalline Form R of Compound (I) (top) and a graph of differential scanning calorimetry (DSC) of crystalline Form R of Compound (I) (bottom). [Figure 12] FIG. 12 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form S of compound (I). [Figure 13]FIG. 13 shows a graph (top) of thermogravimetric analysis (TGA) of crystalline form S of compound (I) and a graph (bottom) of differential scanning calorimetry (DSC) of crystalline form S of compound (I). [Figure 14] FIG. 14 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form T of compound (I). [Figure 15] FIG. 15 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form U of compound (I). [Figure 16] FIG. 16 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline Form V of Compound (I). [Figure 17] FIG. 17 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form W of compound (I). [Figure 18] FIG. 18 shows a graph (top) of thermogravimetric analysis (TGA) of crystalline Form W of Compound (I) and a graph (bottom) of differential scanning calorimetry (DSC) of crystalline Form W of Compound (I). [Figure 19] FIG. 19 shows the powder X-ray diffraction pattern (CuKα, measured at room temperature) of the observed crystalline form X of compound (I). [Figure 20] FIG. 20 shows the powder X-ray diffraction pattern (CuKα, measured at room temperature) of the observed crystalline form Y of compound (I). [Figure 21] FIG. 21 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline Form Z of Compound (I). [Figure 22] FIG. 22 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline Form AA of Compound (I). [Diagram 23] FIG. 23 shows a differential scanning calorimetry (DSC) graph of crystalline Form AA of Compound (I). [Figure 24] FIG. 24 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline form AB of compound (I). [Diagram 25] FIG. 25 shows a differential scanning calorimetry (DSC) graph of crystalline Form AB of Compound (I). [Figure 26]FIG. 26 shows a graph of thermogravimetric analysis (TGA) of crystalline Form AB of Compound (I). [Figure 27] FIG. 27 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline Form AC of Compound (I). [Figure 28] FIG. 28 shows the powder X-ray diffraction patterns (CuKα, measured at room temperature) of the observed crystalline forms AD of compound (I). [Figure 29] FIG. 29 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline Form AE of Compound (I). [Diagram 30] FIG. 30 shows a differential scanning calorimetry (DSC) graph of crystalline Form AE of Compound (I). [Diagram 31] FIG. 31 shows the observed powder X-ray diffraction pattern (CuKα, measured at room temperature) of crystalline Form AF of Compound (I). [Diagram 32] FIG. 32 shows a differential scanning calorimetry (DSC) graph of crystalline Form AF of Compound (I). [Diagram 33] FIG. 33 shows a graph of thermogravimetric analysis (TGA) of crystalline Form AF of Compound (I). [Diagram 34] FIG. 34 shows the powder X-ray diffraction pattern (CuKα, measured at room temperature) of the observed crystalline form AG of compound (I). [Diagram 35] FIG. 35 shows a differential scanning calorimetry (DSC) graph of crystalline Form AG of Compound (I). [Diagram 36] FIG. 36 shows a graph of thermogravimetric analysis (TGA) of crystalline form AG of compound (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The features and advantages of the present invention may be more readily understood by those skilled in the art upon reading the following detailed description. It is understood that, for clarity, certain features of the invention that are described before or after the context of another embodiment may be combined to form a single embodiment. Conversely, various features of the invention that are described in a single embodiment for brevity may also be combined to form subcombinations thereof.

[0012] The names used herein to indicate particular crystalline forms (e.g., "crystalline form L") are merely identifiers interpreted based on the characteristic information provided herein (or in the documents cited herein) and are not intended to be limiting so as to exclude any other substances having similar or identical physical and chemical properties.

[0013] The definitions set forth herein take precedence over definitions set forth in any patents, patent applications, and / or published patent applications incorporated herein by reference.

[0014] All numbers expressing quantities, such as ingredients, weight percentages, temperatures, etc., preceded by the word "about" should be understood as merely approximate values, and numerical values ​​slightly higher or lower than the stated numerical values ​​may be used to obtain substantially the same results as the stated numerical values. Thus, unless otherwise indicated, numerical parameters preceded by the word "about" are approximate values ​​and may vary depending on the desired properties sought to be obtained. At the very least, there is no intention to limit the application of the doctrine of equivalents to the scope of the claims, and each numerical parameter should be understood by applying ordinary rounding techniques in light of at least the number of significant digits stated.

[0015] Any measurements may contain experimental error, which is consistent with the principles of the present invention.

[0016] As used herein, the term "polycrystalline substance" refers to a crystal having the same chemical structure but different configurations of the molecules and / or ions that form the crystal.

[0017] The crystal may be a single-component crystal or a multi-component crystal. A multi-component crystal has more than one type of molecule, and includes salts, solvates (e.g., hydrates), and co-crystals. Depending on various conditions, the exact molar ratio of the components of a multi-component crystal may vary. For example, the molar ratio of the components in a solvate or co-crystal provides information about the general relative amount of each component of the solvate or co-crystal. In some embodiments, the molar ratio may vary by ±0.2% from the stated value or range. For example, a molar ratio of 1:0.5 should be understood to include 1:0.4 and 1:0.6, and all individual ratios therebetween. Similarly, a molar ratio of 1:1 should be understood to include 1:0.8 and 1:1.2, and all individual ratios therebetween.

[0018] As used herein, "hydrate" refers to the inclusion of a stoichiometric or non-stoichiometric amount of water molecules incorporated into a crystal lattice structure. In some embodiments, the stoichiometry can be specified (such as a monohydrate).

[0019] As used herein, "amorphous" refers to a solid form of molecules and / or ions that is not crystalline. Amorphous solids do not exhibit a distinct X-ray diffraction pattern with sharp maxima.

[0020] As used herein, "substantially pure" refers to a crystalline form of a compound that is greater than 90% pure by weight (including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% pure by weight, including purities equal to about 100% by weight) based on the mass of the sample or specimen. The remaining material includes other forms of the compound resulting from the manufacturing process, and / or reaction impurities and / or process impurities. For example, a crystalline form of Compound (I) may be considered to be substantially pure in that it has a purity of 90% by weight or greater, as measured by methods currently known and generally accepted in the art. Here, the remaining material, less than 10% by weight, includes amorphous solids of Compound (I) and / or other crystalline forms and / or reaction impurities and / or process impurities.

[0021] As used herein, a powder X-ray diffraction (PXRD) pattern that "includes" a number of peaks selected from a particular group of peaks is intended to include a PXRD pattern that has other peaks that are not included in the particular group of peaks. For example, a PXRD pattern that includes 4 or more (such as 5 or more) peaks or 2θ values ​​selected from a, b, c, d, e, f, g, and h is intended to include a PXRD pattern that has (a) 4 or more (such as 5 or more) 2θ values ​​selected from a, b, c, d, e, f, g, and h, and (b) 0, 1 or more peaks that are not one of a, b, c, d, e, f, g, and h.

[0022] The presence of reaction and / or process impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, and / or infrared spectroscopy.

[0023] As used herein, the parameter of a unit cell, "the number of molecules per unit cell", refers to the number of molecules of compound (I) in a unit cell.

[0024] Crystalline forms of Compound (I) are described in WO 2018 / 183656 (Crystalline Form A), WO 2019 / 232138 (Crystalline Form B), WO 2020 / 251911 (Crystalline Forms C and D), U.S. Provisional Application No. 63 / 143,769 (Crystalline Form E), and U.S. Provisional Application No. 63 / 167,504 (Crystalline Forms F, G, H, I, J, and K). The present invention generally relates to crystalline forms L, M, N, O, P, Q, R, S, T, U, V, W, X, Y, Z, AA, AB, AC, AD, AE, AF, and AG of Compound (I).

[0025] Crystalline form L of compound (I) In some embodiments, Compound (I) is provided as a crystalline substance comprising crystalline Form L. Crystalline Form L of Compound (I) is a crystalline form comprising Compound (I) and gentisic acid. The molar ratio of Compound (I) to gentisic acid in Crystalline Form L is approximately 1:1. Crystalline Form L may be a non-solvate. [Table 1]

[0026] In some embodiments, crystalline Form L of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 7.5±0.2, 13.1±0.2, 14.0±0.2, 15.1±0.2, 22.3±0.2, and 23.9±0.2, wherein the PXRD pattern of crystalline Form L was measured at room temperature.

[0027] In some embodiments, crystalline Form L of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 7.5±0.2, 13.1±0.2, 14.0±0.2, 15.1±0.2, 22.3±0.2, and 23.9±0.2, wherein the PXRD pattern of crystalline Form L was measured at room temperature.

[0028] In some embodiments, crystalline Form L of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 7.5±0.2, 13.1±0.2, 14.0±0.2, 15.1±0.2, 22.3±0.2, and 23.9±0.2, wherein the PXRD pattern of crystalline Form L is measured at room temperature.

[0029] In some embodiments, crystalline Form L of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 5 or more 2θ values ​​(°) (CuKα) selected from 7.5±0.2, 13.1±0.2, 14.0±0.2, 15.1±0.2, 22.3±0.2, and 23.9±0.2, wherein the PXRD pattern of crystalline Form L is measured at room temperature.

[0030] In certain embodiments, crystalline form L of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.5±0.2 and 15.1±0.2. Wherein the PXRD pattern of crystalline form L is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 13.1±0.2, 14.0±0.2, 22.3±0.2, and 23.9±0.2. For example, in some embodiments, crystalline form L of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.5±0.2, 13.1±0.2, and 15.1±0.2. Wherein the PXRD pattern of crystalline form L is measured at room temperature.

[0031] In certain embodiments, crystalline Form L of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.5±0.2, 15.1±0.2, and 23.9±0.2, wherein the PXRD pattern of crystalline Form L is measured at room temperature.

[0032] In certain embodiments, crystalline Form L of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.5±0.2, 13.1±0.2, 14.0±0.2, and 15.1±0.2, wherein the PXRD pattern of crystalline Form L is measured at room temperature.

[0033] In a further embodiment, crystalline Form L of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.5±0.2, 13.1±0.2, 14.0±0.2, 15.1±0.2, and 22.3±0.2, wherein the PXRD pattern of crystalline Form L is measured at room temperature.

[0034] In a further embodiment, crystalline Form L of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.5±0.2, 13.1±0.2, 14.0±0.2, 15.1±0.2, 22.3±0.2, and 23.9±0.2, wherein the PXRD pattern of crystalline Form L is measured at room temperature.

[0035] In certain embodiments, crystalline Form L of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0036] In some embodiments, the crystalline form L of Compound (I) is characterized by having an endothermic peak with an onset temperature in the range of approximately 210°C to 220°C. In further embodiments, the endothermic peak has an onset temperature of about 215°C. For example, in some embodiments, the crystalline form L of Compound (I) is characterized by an onset temperature of the endothermic peak in the range of about 210°C to about 220°C in a differential scanning calorimetry (DSC) graph. In certain embodiments, the onset temperature of the endothermic peak in the differential scanning calorimetry (DSC) graph is about 215°C. It should be understood that in some embodiments, endotherm may not be detected.

[0037] In certain embodiments, crystalline Form L of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form L measured at room temperature contains 2θ values ​​(°) (CuKα) of 7.5±0.2 and 15.1±0.2, and (ii) the endothermic peak onset temperature is in the range of approximately 210° C. to 220° C. In further embodiments, the endothermic peak onset temperature is about 215° C.

[0038] In certain embodiments, crystalline Form L of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form L measured at room temperature contains 2θ values ​​(°) (CuKα) of 7.5±0.2, 13.1±0.2, and 15.1±0.2, and (ii) the endothermic peak onset temperature is in the range of approximately 210° C. to 220° C. In further embodiments, the endothermic peak onset temperature is about 215° C.

[0039] In certain embodiments, crystalline Form L of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form L measured at room temperature contains 2θ values ​​(°) (CuKα) of 7.5±0.2, 15.1±0.2, and 23.9±0.2, and (ii) the endothermic peak onset temperature is in the range of approximately 210° C. to 220° C. In further embodiments, the endothermic peak onset temperature is about 215° C.

[0040] In some embodiments, crystalline Form L of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph substantially in accordance with the graph shown in FIG. 2 (bottom).

[0041] In certain embodiments, crystalline Form L of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form L measured at room temperature comprises two or more 2θ values ​​(°) (CuKα) selected from 7.5±0.2, 13.1±0.2, 14.0±0.2, 15.1±0.2, 22.3±0.2, and 23.9±0.2, and (ii) the differential scanning calorimetry (DSC) graph substantially corresponds to the graph shown in FIG. 2 (bottom).

[0042] In some embodiments, crystalline form L of Compound (I) is characterized by a mass loss of less than 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 150° C. (e.g., from room temperature). In certain embodiments, crystalline form L of Compound (I) is characterized by a mass loss of less than 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 175° C. In further embodiments, crystalline form L of Compound (I) is characterized by a mass loss of less than about 1.0%, less than about 0.5%, or in certain embodiments, less than about 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 200° C.

[0043] In certain embodiments, crystalline Form L of Compound (I) substantially conforms to the thermogravimetric analysis (TGA) graph depicted in FIG. 2 (top).

[0044] In some embodiments, crystalline Form L of Compound (I) is substantially pure. For example, crystalline Form L of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, with the remainder of the material containing other forms of the compound and / or reaction impurities and / or process impurities.

[0045] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form L. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form L.

[0046] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form L.

[0047] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form L of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0048] In certain embodiments, the pharmaceutical composition comprises a substantially pure crystalline Form L of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0049] In certain embodiments, crystalline Form L of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0050] In some embodiments, the pharmaceutical composition comprises crystalline Form L of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0051] Crystalline form M of compound (I) In some embodiments, Compound (I) is provided as a crystalline material comprising Form M. Form M of Compound (I) is a crystalline form of the hydrobromic acid (HBr) salt. - ) is approximately 1:2. Crystalline Form M may be a non-solvate. [Table 2]

[0052] In some embodiments, crystalline Form M of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 9.8±0.2, 12.3±0.2, 16.5±0.2, 21.0±0.2, and 25.1±0.2, wherein the PXRD pattern of crystalline Form M was measured at room temperature.

[0053] In some embodiments, crystalline Form M of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 9.8±0.2, 12.3±0.2, 16.5±0.2, 21.0±0.2, and 25.1±0.2, wherein the PXRD pattern of crystalline Form M was measured at room temperature.

[0054] In some embodiments, crystalline Form M of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 9.8±0.2, 12.3±0.2, 16.5±0.2, 21.0±0.2, and 25.1±0.2, wherein the PXRD pattern of crystalline Form M was measured at room temperature.

[0055] In certain embodiments, crystalline Form M of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 9.8±0.2 and 12.3±0.2, wherein the PXRD pattern of crystalline Form M is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 16.5±0.2, 21.0±0.2, and 25.1±0.2.

[0056] In certain embodiments, crystalline Form M of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 12.3±0.2 and 16.5±0.2, wherein the PXRD pattern of crystalline Form M is measured at room temperature.

[0057] In a further embodiment, crystalline Form M of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 9.8±0.2, 12.3±0.2, and 16.5±0.2, wherein the PXRD pattern of crystalline Form M is measured at room temperature.

[0058] In a further embodiment, crystalline Form M of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 9.8±0.2, 12.3±0.2, 16.5±0.2, and 21.0±0.2, wherein the PXRD pattern of crystalline Form M is measured at room temperature.

[0059] In a further embodiment, crystalline Form M of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 9.8±0.2, 12.3±0.2, 16.5±0.2, 21.0±0.2, and 25.1±0.2, wherein the PXRD pattern of crystalline Form M was measured at room temperature.

[0060] In certain embodiments, crystalline Form M of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0061] In some embodiments, the crystalline form M of Compound (I) is characterized by having a maximum endothermic peak in the range of approximately 171° C. to 181° C. For example, in some embodiments, the crystalline form M of Compound (I) is characterized by having a maximum endothermic peak in the range of about 171° C. to about 181° C. in a differential scanning calorimetry (DSC) graph. It should be understood that in some embodiments, endothermic heat may not be detected.

[0062] In certain embodiments, crystalline Form M of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of Form M measured at room temperature contains 2θ values ​​(°) (CuKα) of 9.8±0.2 and 12.3±0.2, and (ii) has a maximum endothermic peak in the range of approximately 171°C to 181°C.

[0063] In certain embodiments, crystalline Form M of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form M measured at room temperature contains 2θ values ​​(°) (CuKα) of 9.8±0.2, 12.3±0.2, and 16.5±0.2, and (ii) has a maximum endothermic peak in the range of approximately 171°C to 181°C.

[0064] In some embodiments, crystalline Form M of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph substantially in accordance with the graph shown in Figure 4 (bottom).

[0065] In certain embodiments, crystalline Form M of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form M measured at room temperature comprises two or more 2θ values ​​(°) (CuKα) selected from 9.8±0.2, 12.3±0.2, 16.5±0.2, 21.0±0.2, and 25.1±0.2, and (ii) the differential scanning calorimetry (DSC) graph substantially corresponds to the graph shown in FIG. 4 (bottom).

[0066] In some embodiments, crystalline form M of Compound (I) is characterized by a mass loss of less than 0.5% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 100° C. (e.g., from room temperature). In certain embodiments, crystalline form M of Compound (I) is characterized by a mass loss of less than 0.5% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 120° C. In certain embodiments, crystalline form M of Compound (I) is characterized by a mass loss of less than about 1.0%, less than about 0.5%, or in further embodiments, less than about 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 120° C.

[0067] In certain embodiments, crystalline Form M of Compound (I) substantially conforms to the thermogravimetric analysis (TGA) graph depicted in FIG. 4 (top).

[0068] In some embodiments, crystalline Form M of Compound (I) is substantially pure. For example, crystalline Form M of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, with the remainder of the material containing other forms of the compound and / or reaction and / or process impurities.

[0069] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form M. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form M.

[0070] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is crystalline Form M.

[0071] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form M of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0072] In certain embodiments, the pharmaceutical composition comprises a substantially pure crystalline Form M of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0073] In certain embodiments, crystalline Form M of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0074] In some embodiments, the pharmaceutical composition comprises crystalline Form M of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0075] Crystalline form N of compound (I) In some embodiments, Compound (I) is provided as a crystalline substance comprising Form N. Form N of Compound (I) is a crystalline form of a nitrate salt. NO3 of Compound (I) in Form N - The molar ratio of to is approximately 1:2. Crystalline Form N may be a non-solvate. [Table 3]

[0076] In some embodiments, crystalline Form N of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 8.1±0.2, 9.0±0.2, 15.8±0.2, 22.6±0.2, and 25.0±0.2, wherein the PXRD pattern of crystalline Form N is measured at room temperature.

[0077] In some embodiments, crystalline Form N of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 8.1±0.2, 9.0±0.2, 15.8±0.2, 22.6±0.2, and 25.0±0.2, wherein the PXRD pattern of crystalline Form N is measured at room temperature.

[0078] In some embodiments, crystalline Form N of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 8.1±0.2, 9.0±0.2, 15.8±0.2, 22.6±0.2, and 25.0±0.2, wherein the PXRD pattern of crystalline Form N is measured at room temperature.

[0079] In certain embodiments, crystalline Form N of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.1±0.2 and 9.0±0.2, wherein the PXRD pattern of crystalline Form N is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 15.8±0.2, 22.6±0.2, and 25.0±0.2.

[0080] In certain embodiments, crystalline Form N of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 9.0±0.2 and 22.6±0.2, wherein the PXRD pattern of crystalline Form N is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 8.1±0.2, 15.8±0.2, and 25.0±0.2.

[0081] In a further embodiment, crystalline Form N of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.1±0.2, 9.0±0.2, and 22.6±0.2, wherein the PXRD pattern of crystalline Form N is measured at room temperature.

[0082] In certain embodiments, crystalline Form N of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.1±0.2, 9.0±0.2, and 15.8±0.2, wherein the PXRD pattern of crystalline Form N is measured at room temperature.

[0083] In a further embodiment, crystalline Form N of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.1±0.2, 9.0±0.2, 15.8±0.2, and 22.6±0.2, wherein the PXRD pattern of crystalline Form N is measured at room temperature.

[0084] In a further embodiment, crystalline Form N of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.1±0.2, 9.0±0.2, 15.8±0.2, 22.6±0.2, and 25.0±0.2, wherein the PXRD pattern of crystalline Form N is measured at room temperature.

[0085] In certain embodiments, crystalline Form N of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0086] In some embodiments, the crystalline form N of Compound (I) is characterized by having a maximum endothermic peak in the range of approximately 166° C. to 176° C. For example, in some embodiments, the crystalline form N of Compound (I) is characterized by having a maximum endothermic peak in the range of about 166° C. to about 176° C. in a differential scanning calorimetry (DSC) graph. It should be understood that in some embodiments, endothermic heat may not be detected.

[0087] In certain embodiments, crystalline Form N of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form N measured at room temperature contains 2θ values ​​(°) (CuKα) of 8.1±0.2 and 9.0±0.2, and (ii) has a maximum endothermic peak in the range of approximately 166°C to 176°C.

[0088] In certain embodiments, crystalline Form N of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form N measured at room temperature contains 2θ values ​​(°) (CuKα) of 8.1±0.2, 9.0±0.2, and 15.8±0.2, and (ii) has a maximum endothermic peak in the range of approximately 166°C to 176°C.

[0089] In some embodiments, crystalline Form N of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph substantially in accordance with the graph shown in Figure 6 (bottom).

[0090] In certain embodiments, crystalline Form N of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form N measured at room temperature comprises two or more 2θ values ​​(°) (CuKα) selected from 8.1±0.2, 9.0±0.2, 15.8±0.2, 22.6±0.2, and 25.0±0.2, and (ii) the differential scanning calorimetry (DSC) graph substantially corresponds to the graph shown in FIG. 6 (bottom).

[0091] In some embodiments, crystalline Form N of Compound (I) is characterized by a mass loss of less than 0.5% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 100° C. (e.g., from room temperature). In certain embodiments, crystalline Form N of Compound (I) is characterized by a mass loss of less than 0.5% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 120° C. In certain embodiments, crystalline Form N of Compound (I) is characterized by a mass loss of less than about 1.0%, less than about 0.5%, or in further embodiments, less than about 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 120° C.

[0092] In certain embodiments, crystalline Form N of Compound (I) substantially conforms to the thermogravimetric analysis (TGA) graph depicted in FIG. 6 (top).

[0093] In some embodiments, crystalline Form N of Compound (I) is substantially pure. For example, crystalline Form N of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, while the remainder of the material contains other forms of the compound and / or reaction impurities and / or process impurities.

[0094] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form N. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form N.

[0095] Also, certain embodiments provide a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form N.

[0096] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form N of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0097] In certain embodiments, the pharmaceutical composition comprises substantially pure crystalline Form N of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0098] In certain embodiments, crystalline Form N of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0099] In some embodiments, the pharmaceutical composition comprises crystalline Form N of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0100] Crystalline form O of compound (I) In some embodiments, Compound (I) is provided as a crystalline material comprising Form O. Form O of Compound (I) is a crystalline form of a p-toluenesulfonic acid (TSA) salt. The molar ratio of Compound (I) to p-toluenesulfonic acid in Form O is approximately 1:1. [Table 4]

[0101] In some embodiments, crystalline Form O of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 7.3±0.2, 10.1±0.2, 15.1±0.2, 17.2±0.2, and 25.2±0.2, wherein the PXRD pattern of crystalline Form O was measured at room temperature.

[0102] In some embodiments, crystalline Form O of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 7.3±0.2, 10.1±0.2, 15.1±0.2, 17.2±0.2, and 25.2±0.2, wherein the PXRD pattern of crystalline Form O was measured at room temperature.

[0103] In some embodiments, crystalline Form O of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 7.3±0.2, 10.1±0.2, 15.1±0.2, 17.2±0.2, and 25.2±0.2, wherein the PXRD pattern of crystalline Form O was measured at room temperature.

[0104] In certain embodiments, crystalline Form O of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.3±0.2 and 10.1±0.2, wherein the PXRD pattern of crystalline Form O is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 15.1±0.2, 17.2±0.2, and 25.2±0.2.

[0105] In certain embodiments, crystalline Form O of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.3±0.2 and 15.1±0.2, wherein the PXRD pattern of crystalline Form O is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 10.1±0.2, 17.2±0.2, and 25.2±0.2.

[0106] In certain embodiments, crystalline Form O of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.3±0.2, 10.1±0.2, and 15.1±0.2, wherein the PXRD pattern of crystalline Form O is measured at room temperature.

[0107] In a further embodiment, crystalline Form O of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.3±0.2, 10.1±0.2, 15.1±0.2, and 17.2±0.2, wherein the PXRD pattern of crystalline Form O is measured at room temperature.

[0108] In further embodiments, crystalline Form O of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.3±0.2, 10.1±0.2, 15.1±0.2, 17.2±0.2, and 25.2±0.2, wherein the PXRD pattern of crystalline Form O was measured at room temperature.

[0109] In certain embodiments, crystalline Form O of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0110] In some embodiments, crystalline Form O of Compound (I) is substantially pure. For example, crystalline Form O of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, while the remainder of the material contains other forms of the compound and / or reaction impurities and / or process impurities.

[0111] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form O. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form O.

[0112] Also, certain embodiments provide a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is crystalline Form O.

[0113] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form O of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0114] In certain embodiments, the pharmaceutical composition comprises a substantially pure crystalline Form O of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0115] In certain embodiments, crystalline Form O of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0116] In some embodiments, the pharmaceutical composition comprises crystalline Form O of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0117] Crystalline form P of compound (I) In some embodiments, Compound (I) is provided as a crystalline material, including Form P. Form P of Compound (I) is a crystalline form of the hydrobromic acid (HBr) salt. The molar ratio of Compound (I) to bromide (Br-) in Form P is approximately 1:2. Form P may be a hydrate. [Table 5]

[0118] In some embodiments, crystalline Form P of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 7.4±0.2, 8.6±0.2, 14.9±0.2, 18.8±0.2, and 22.9±0.2, wherein the PXRD pattern of crystalline Form P was measured at room temperature.

[0119] In some embodiments, crystalline Form P of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 7.4±0.2, 8.6±0.2, 14.9±0.2, 18.8±0.2, and 22.9±0.2, wherein the PXRD pattern of crystalline Form P was measured at room temperature.

[0120] In some embodiments, crystalline Form P of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 7.4±0.2, 8.6±0.2, 14.9±0.2, 18.8±0.2, and 22.9±0.2, wherein the PXRD pattern of crystalline Form P was measured at room temperature.

[0121] In certain embodiments, crystalline Form P of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.4±0.2 and 8.6±0.2, wherein the PXRD pattern of crystalline Form P is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 14.9±0.2, 18.8±0.2, and 22.9±0.2.

[0122] In certain embodiments, crystalline Form P of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.4±0.2, 8.6±0.2, and 14.9±0.2, wherein the PXRD pattern of crystalline Form P is measured at room temperature.

[0123] In a further embodiment, crystalline Form P of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.4±0.2, 8.6±0.2, 14.9±0.2, and 18.8±0.2, wherein the PXRD pattern of crystalline Form P is measured at room temperature.

[0124] In a further embodiment, crystalline Form P of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.4±0.2, 8.6±0.2, 14.9±0.2, 18.8±0.2, and 22.9±0.2, wherein the PXRD pattern of crystalline Form P was measured at room temperature.

[0125] In certain embodiments, crystalline Form P of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0126] In some embodiments, crystalline Form P of Compound (I) is substantially pure. For example, crystalline Form P of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, with the remainder of the material containing other forms of the compound and / or reaction and / or process impurities.

[0127] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form P. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight of crystalline Form P, preferably at least about 95% by weight, more preferably at least about 99% by weight.

[0128] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form P.

[0129] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form P of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0130] In certain embodiments, the pharmaceutical composition comprises substantially pure crystalline Form P of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0131] In certain embodiments, crystalline Form P of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0132] In some embodiments, the pharmaceutical composition comprises crystalline Form P of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0133] Crystalline form Q of compound (I) In some embodiments, Compound (I) is provided as a crystalline material comprising Crystalline Form Q. Crystalline Form Q of Compound (I) is a crystalline form comprising Compound (I) and malonic acid. [Table 6]

[0134] In some embodiments, crystalline Form Q of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 5.4±0.2, 9.6±0.2, 11.6±0.2, 20.2±0.2, 21.2±0.2, and 23.8±0.2, wherein the PXRD pattern of crystalline Form Q was measured at room temperature.

[0135] In some embodiments, crystalline Form Q of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 5.4±0.2, 9.6±0.2, 11.6±0.2, 20.2±0.2, 21.2±0.2, and 23.8±0.2, wherein the PXRD pattern of crystalline Form Q was measured at room temperature.

[0136] In some embodiments, crystalline Form Q of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 5.4±0.2, 9.6±0.2, 11.6±0.2, 20.2±0.2, 21.2±0.2, and 23.8±0.2, wherein the PXRD pattern of crystalline Form Q was measured at room temperature.

[0137] In some embodiments, crystalline Form Q of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 5 or more 2θ values ​​(°) (CuKα) selected from 5.4±0.2, 9.6±0.2, 11.6±0.2, 20.2±0.2, 21.2±0.2, and 23.8±0.2, wherein the PXRD pattern of crystalline Form Q was measured at room temperature.

[0138] In certain embodiments, crystalline Form Q of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 9.6±0.2 and 11.6±0.2, wherein the PXRD pattern of crystalline Form Q is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 5.4±0.2, 20.2±0.2, 21.2±0.2, and 23.8±0.2.

[0139] In certain embodiments, crystalline Form Q of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 5.4±0.2 and 9.6±0.2, wherein the PXRD pattern of crystalline Form Q is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 11.6±0.2, 20.2±0.2, 21.2±0.2, and 23.8±0.2.

[0140] In certain embodiments, crystalline Form Q of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 5.4±0.2, 9.6±0.2, and 11.6±0.2, wherein the PXRD pattern of crystalline Form Q is measured at room temperature.

[0141] In a further embodiment, crystalline Form Q of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 5.4±0.2, 9.6±0.2, 11.6±0.2, and 20.2±0.2, wherein the PXRD pattern of crystalline Form Q was measured at room temperature.

[0142] In further embodiments, crystalline Form Q of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 5.4±0.2, 9.6±0.2, 11.6±0.2, 20.2±0.2, and 21.2±0.2, wherein the PXRD pattern of crystalline Form Q was measured at room temperature.

[0143] In further embodiments, crystalline Form Q of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 5.4±0.2, 9.6±0.2, 11.6±0.2, 20.2±0.2, 21.2±0.2, and 23.8±0.2, wherein the PXRD pattern of crystalline Form Q was measured at room temperature.

[0144] In certain embodiments, crystalline Form Q of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0145] In some embodiments, crystalline Form Q of Compound (I) is substantially pure. For example, crystalline Form Q of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, with the remainder of the material containing other forms of the compound and / or reaction and / or process impurities.

[0146] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form Q. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form Q.

[0147] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form Q.

[0148] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form Q of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0149] In certain embodiments, the pharmaceutical composition comprises a substantially pure crystalline Form Q of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0150] In certain embodiments, crystalline Form Q of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0151] In some embodiments, the pharmaceutical composition comprises crystalline Form Q of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0152] Crystalline form R of compound (I) In some embodiments, Compound (I) is provided as a crystalline substance, including Form R. Form R of Compound (I) is a crystalline form of 1,2-ethanesulfonic acid salt. The molar ratio of Compound (I) to 1,2-ethanesulfonic acid in Form R is approximately 2:1. Form R may be a non-solvate. [Table 7]

[0153] In some embodiments, crystalline Form R of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 9.5±0.2, 10.0±0.2, 16.4±0.2, 17.2±0.2, 22.0±0.2, and 22.8±0.2, wherein the PXRD pattern of crystalline Form R was measured at room temperature.

[0154] In some embodiments, crystalline Form R of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 9.5±0.2, 10.0±0.2, 16.4±0.2, 17.2±0.2, 22.0±0.2, and 22.8±0.2, wherein the PXRD pattern of crystalline Form R was measured at room temperature.

[0155] In some embodiments, crystalline Form R of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 9.5±0.2, 10.0±0.2, 16.4±0.2, 17.2±0.2, 22.0±0.2, and 22.8±0.2, wherein the PXRD pattern of crystalline Form R was measured at room temperature.

[0156] In some embodiments, crystalline Form R of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 5 or more 2θ values ​​(°) (CuKα) selected from 9.5±0.2, 10.0±0.2, 16.4±0.2, 17.2±0.2, 22.0±0.2, and 22.8±0.2, wherein the PXRD pattern of crystalline Form R was measured at room temperature.

[0157] In certain embodiments, crystalline Form R of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 9.5±0.2 and 10.0±0.2, wherein the PXRD pattern of crystalline Form R is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 16.4±0.2, 17.2±0.2, 22.0±0.2, and 22.8±0.2.

[0158] In certain embodiments, crystalline Form R of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 9.5±0.2, 10.0±0.2, and 16.4±0.2., wherein the PXRD pattern of crystalline Form R is measured at room temperature.

[0159] In a further embodiment, crystalline Form R of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 9.5±0.2, 10.0±0.2, 16.4±0.2, and 17.2±0.2, wherein the PXRD pattern of crystalline Form R is measured at room temperature.

[0160] In a further embodiment, crystalline Form R of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 9.5±0.2, 10.0±0.2, 16.4±0.2, 17.2±0.2, and 22.0±0.2, wherein the PXRD pattern of crystalline Form R is measured at room temperature.

[0161] In a further embodiment, crystalline Form R of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 9.5±0.2, 10.0±0.2, 16.4±0.2, 17.2±0.2, 22.0±0.2, and 22.8±0.2, wherein the PXRD pattern of crystalline Form R is measured at room temperature.

[0162] In certain embodiments, crystalline Form R of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0163] In some embodiments, the crystalline form R of Compound (I) is characterized by having a maximum endothermic peak in the range of approximately 280° C. to 290° C. For example, in some embodiments, the crystalline form R of Compound (I) is characterized by having a maximum endothermic peak in the range of about 280° C. to about 290° C. in a differential scanning calorimetry (DSC) graph. It should be understood that in some embodiments, endothermic heat may not be detected.

[0164] In certain embodiments, crystalline Form R of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form R measured at room temperature contains 2θ values ​​(°) (CuKα) of 9.5±0.2 and 10.0±0.2, and (ii) has a maximum endothermic peak in the range of approximately 280°C to 290°C.

[0165] In certain embodiments, crystalline Form R of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form R measured at room temperature contains 2θ values ​​(°) (CuKα) of 9.5±0.2, 10.0±0.2, and 16.4±0.2, and (ii) has a maximum endothermic peak in the range of approximately 280°C to 290°C.

[0166] In some embodiments, crystalline Form R of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph substantially in accordance with the graph shown in Figure 11 (bottom).

[0167] In certain embodiments, crystalline Form R of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form R measured at room temperature comprises two or more 2θ values ​​(°) (CuKα) selected from 9.5±0.2, 10.0±0.2, 16.4±0.2, 17.2±0.2, 22.0±0.2, and 22.8±0.2, and (ii) the differential scanning calorimetry (DSC) graph substantially corresponds to the graph shown in FIG. 11 (bottom).

[0168] In some embodiments, crystalline Form R of Compound (I) is characterized by a mass loss of less than 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 150° C. (e.g., from room temperature). In certain embodiments, crystalline Form R of Compound (I) is characterized by a mass loss of less than 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 175° C. In certain embodiments, crystalline Form R of Compound (I) is characterized by a mass loss of less than about 1.0%, less than about 0.5%, or in further embodiments, less than about 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 200° C.

[0169] In certain embodiments, crystalline Form R of Compound (I) is substantially in accordance with the thermogravimetric analysis (TGA) graph depicted in FIG. 11 (top).

[0170] In some embodiments, crystalline Form R of Compound (I) is substantially pure. For example, crystalline Form R of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, while the remainder of the material contains other forms of the compound and / or reaction and / or process impurities.

[0171] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form R. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form R.

[0172] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is crystalline Form R.

[0173] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form R of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0174] In certain embodiments, the pharmaceutical composition comprises a substantially pure crystalline Form R of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0175] In certain embodiments, crystalline Form R of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0176] In some embodiments, the pharmaceutical composition comprises crystalline Form R of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0177] Crystalline form S of compound (I) In some embodiments, Compound (I) is provided as a crystalline substance, including Form S. Form S of Compound (I) is a crystalline form of 2-hydroxyethanesulfonic acid salt. The molar ratio of Compound (I) to 2-hydroxyethanesulfonic acid in Form S is approximately 1:1. Form S may be a non-solvate. [Table 8]

[0178] In some embodiments, crystalline Form S of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 8.4±0.2, 9.6±0.2, 19.3±0.2, 23.7±0.2, and 24.7±0.2, wherein the PXRD pattern of crystalline Form S was measured at room temperature.

[0179] In some embodiments, crystalline Form S of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 8.4±0.2, 9.6±0.2, 19.3±0.2, 23.7±0.2, and 24.7±0.2, wherein the PXRD pattern of crystalline Form S is measured at room temperature.

[0180] In some embodiments, crystalline Form S of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 8.4±0.2, 9.6±0.2, 19.3±0.2, 23.7±0.2, and 24.7±0.2, wherein the PXRD pattern of crystalline Form S is measured at room temperature.

[0181] In certain embodiments, crystalline Form S of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.4±0.2 and 9.6±0.2, wherein the PXRD pattern of crystalline Form S is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 19.3±0.2, 23.7±0.2, and 24.7±0.2.

[0182] In certain embodiments, crystalline Form S of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.4±0.2, 9.6±0.2, and 24.7±0.2, wherein the PXRD pattern of crystalline Form S is measured at room temperature.

[0183] In certain embodiments, crystalline Form S of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.4±0.2, 9.6±0.2, and 19.3±0.2, wherein the PXRD pattern of crystalline Form S is measured at room temperature.

[0184] In a further embodiment, crystalline Form S of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.4±0.2, 9.6±0.2, 19.3±0.2, and 23.7±0.2, wherein the PXRD pattern of crystalline Form S is measured at room temperature.

[0185] In a further embodiment, crystalline Form S of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.4±0.2, 9.6±0.2, 19.3±0.2, 23.7±0.2, and 24.7±0.2, wherein the PXRD pattern of crystalline Form S is measured at room temperature.

[0186] In certain embodiments, crystalline Form S of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0187] In some embodiments, the crystalline form S of Compound (I) is characterized by having a maximum endothermic peak at a temperature above about 180° C. In certain embodiments, the crystalline form S of Compound (I) is characterized by having a maximum endothermic peak in the range of approximately 183° C. to 193° C. For example, in some embodiments, the crystalline form S of Compound (I) is characterized by having a maximum endothermic peak in the range of about 183° C. to about 193° C. in the differential scanning calorimetry (DSC) graph. It should be understood that in some embodiments, endotherms may not be detected.

[0188] In certain embodiments, crystalline Form S of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form S measured at room temperature contains 2θ values ​​(°) (CuKα) of 8.4±0.2 and 9.6±0.2, and (ii) has a maximum endothermic peak in the range of approximately 183°C to 193°C.

[0189] In certain embodiments, crystalline Form S of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form S measured at room temperature contains 2θ values ​​(°) (CuKα) of 8.4±0.2, 9.6±0.2, and 19.3±0.2, and (ii) has a maximum endothermic peak in the range of approximately 183°C to 193°C.

[0190] In certain embodiments, crystalline Form S of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form S measured at room temperature contains 2θ values ​​(°) (CuKα) of 8.4±0.2, 9.6±0.2, and 24.7±0.2, and (ii) has a maximum endothermic peak in the range of approximately 183°C to 193°C.

[0191] In some embodiments, crystalline Form S of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph substantially in accordance with the graph shown in Figure 13 (bottom).

[0192] In certain embodiments, crystalline Form S of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form S measured at room temperature comprises two or more 2θ values ​​(°) (CuKα) selected from 8.4±0.2, 9.6±0.2, 19.3±0.2, 23.7±0.2, and 24.7±0.2, and (ii) the differential scanning calorimetry (DSC) graph substantially corresponds to the graph shown in FIG. 13 (bottom).

[0193] In some embodiments, the crystalline form S of Compound (I) is characterized by a mass loss of less than 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 150° C. (e.g., from room temperature). In certain embodiments, the crystalline form S of Compound (I) is characterized by a mass loss of less than 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 175° C. In certain embodiments, the crystalline form S of Compound (I) is characterized by a mass loss of less than about 1.0%, less than about 0.5%, or in further embodiments, less than about 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 200° C.

[0194] In certain embodiments, crystalline Form S of Compound (I) is substantially in accordance with the thermogravimetric analysis (TGA) graph depicted in FIG. 13 (top).

[0195] In some embodiments, crystalline Form S of Compound (I) is substantially pure. For example, crystalline Form S of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, with the remainder of the material containing other forms of the compound and / or reaction impurities and / or process impurities.

[0196] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form S. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form S.

[0197] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form S.

[0198] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form S of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0199] In certain embodiments, the pharmaceutical composition comprises a substantially pure crystalline Form S of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0200] In certain embodiments, crystalline Form S of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0201] In some embodiments, the pharmaceutical composition comprises crystalline Form S of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0202] Crystalline form T of compound (I) In some embodiments, Compound (I) comprises a crystalline form T provided as a crystalline substance. Crystalline form T of Compound (I) is a crystalline form comprising Compound (I) and maleic acid. The molar ratio of Compound (I) to maleic acid in Crystalline form T is approximately 1:1. [Table 9]

[0203] In some embodiments, crystalline Form T of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 10.7±0.2, 11.0±0.2, 12.7±0.2, 18.5±0.2, and 23.9±0.2, wherein the PXRD pattern of crystalline Form T is measured at room temperature.

[0204] In some embodiments, crystalline Form T of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 10.7±0.2, 11.0±0.2, 12.7±0.2, 18.5±0.2, and 23.9±0.2, wherein the PXRD pattern of crystalline Form T is measured at room temperature.

[0205] In some embodiments, crystalline Form T of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 10.7±0.2, 11.0±0.2, 12.7±0.2, 18.5±0.2, and 23.9±0.2, wherein the PXRD pattern of crystalline Form T is measured at room temperature.

[0206] In certain embodiments, crystalline Form T of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 10.7±0.2 and 11.0±0.2, wherein the PXRD pattern of crystalline Form T is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 12.7±0.2, 18.5±0.2, and 23.9±0.2.

[0207] In certain embodiments, crystalline Form T of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 10.7±0.2, 11.0±0.2, and 23.9±0.2, wherein the PXRD pattern of crystalline Form T is measured at room temperature.

[0208] In certain embodiments, crystalline Form T of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 10.7±0.2, 11.0±0.2, and 12.7±0.2, wherein the PXRD pattern of crystalline Form T is measured at room temperature.

[0209] In a further embodiment, crystalline Form T of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 10.7±0.2, 11.0±0.2, 12.7±0.2, and 18.5±0.2, wherein the PXRD pattern of crystalline Form T is measured at room temperature.

[0210] In a further embodiment, crystalline Form T of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 10.7±0.2, 11.0±0.2, 12.7±0.2, 18.5±0.2, and 23.9±0.2, wherein the PXRD pattern of crystalline Form T is measured at room temperature.

[0211] In certain embodiments, crystalline Form T of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0212] In some embodiments, crystalline Form T of Compound (I) is substantially pure. For example, crystalline Form T of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, with the remainder of the material containing other forms of the compound and / or reaction impurities and / or process impurities.

[0213] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form T. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form T.

[0214] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form T.

[0215] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form T of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0216] In certain embodiments, the pharmaceutical composition comprises substantially pure crystalline Form T of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0217] In certain embodiments, crystalline Form T of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0218] In some embodiments, the pharmaceutical composition comprises crystalline Form T of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0219] Crystalline form U of compound (I) In some embodiments, Compound (I) comprises a crystalline form U provided as a crystalline material. The crystalline form U of Compound (I) is a crystalline form of naphthalene-1,5-disulfonic acid salt. The molar ratio of Compound (I) to naphthalene-1,5-disulfonic acid in the crystalline form U is approximately 1:2. The crystalline form U may be a hydrate. [Table 10]

[0220] In some embodiments, crystalline Form U of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 7.2±0.2, 9.1±0.2, 10.2±0.2, 13.4±0.2, and 18.5±0.2, wherein the PXRD pattern of crystalline Form U was measured at room temperature.

[0221] In some embodiments, crystalline Form U of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 7.2±0.2, 9.1±0.2, 10.2±0.2, 13.4±0.2, and 18.5±0.2, wherein the PXRD pattern of crystalline Form U was measured at room temperature.

[0222] In some embodiments, crystalline Form U of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 7.2±0.2, 9.1±0.2, 10.2±0.2, 13.4±0.2, and 18.5±0.2, wherein the PXRD pattern of crystalline Form U was measured at room temperature.

[0223] In certain embodiments, crystalline Form U of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.2±0.2 and 9.1±0.2. The PXRD pattern of crystalline Form U is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 10.2±0.2, 13.4±0.2, and 18.5±0.2.

[0224] In certain embodiments, crystalline Form U of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.2±0.2, 9.1±0.2, and 18.5±0.2, wherein the PXRD pattern of crystalline Form U is measured at room temperature.

[0225] In certain embodiments, crystalline Form U of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.2±0.2, 9.1±0.2, and 10.2±0.2, wherein the PXRD pattern of crystalline Form U is measured at room temperature.

[0226] In a further embodiment, crystalline Form U of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.2±0.2, 9.1±0.2, 10.2±0.2, and 13.4±0.2, wherein the PXRD pattern of crystalline Form U was measured at room temperature.

[0227] In a further embodiment, crystalline Form U of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.2±0.2, 9.1±0.2, 10.2±0.2, 13.4±0.2, and 18.5±0.2, wherein the PXRD pattern of crystalline Form U was measured at room temperature.

[0228] In certain embodiments, crystalline Form U of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0229] In some embodiments, crystalline Form U of Compound (I) is substantially pure. For example, crystalline Form U of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, while the remainder of the material contains other forms of the compound and / or reaction impurities and / or process impurities.

[0230] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form U. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form U.

[0231] Also, certain embodiments provide a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form U.

[0232] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form U of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0233] In certain embodiments, the pharmaceutical composition comprises a substantially pure crystalline Form U of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0234] In certain embodiments, crystalline Form U of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0235] In some embodiments, the pharmaceutical composition comprises crystalline Form U of Compound (I) and other solid forms of Compound (I). The other solid forms may be, for example, other crystalline and / or amorphous solids of Compound (I).

[0236] Crystalline Form V of Compound (I) In some embodiments, Compound (I) is provided as a crystalline material comprising Form V. Form V of Compound (I) is a crystalline form of the nitrate salt. The NO3 - The molar ratio of is approximately 1:2. [Table 11]

[0237] In some embodiments, crystalline Form V of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 6.3±0.2, 9.1±0.2, 16.9±0.2, 25.2±0.2, 26.4±0.2, and 27.4±0.2, wherein the PXRD pattern of crystalline Form V was measured at room temperature.

[0238] In some embodiments, crystalline Form V of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 6.3±0.2, 9.1±0.2, 16.9±0.2, 25.2±0.2, 26.4±0.2, and 27.4±0.2, wherein the PXRD pattern of crystalline Form V was measured at room temperature.

[0239] In some embodiments, crystalline Form V of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 6.3±0.2, 9.1±0.2, 16.9±0.2, 25.2±0.2, 26.4±0.2, and 27.4±0.2, wherein the PXRD pattern of crystalline Form V was measured at room temperature.

[0240] In some embodiments, crystalline Form V of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 5 or more 2θ values ​​(°) (CuKα) selected from 6.3±0.2, 9.1±0.2, 16.9±0.2, 25.2±0.2, 26.4±0.2, and 27.4±0.2, wherein the PXRD pattern of crystalline Form V was measured at room temperature.

[0241] In certain embodiments, crystalline Form V of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.3±0.2 and 9.1±0.2, wherein the PXRD pattern of crystalline Form V is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 16.9±0.2, 25.2±0.2, 26.4±0.2, and 27.4±0.2.

[0242] In certain embodiments, crystalline Form V of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.3±0.2, 9.1±0.2, and 16.9±0.2, wherein the PXRD pattern of crystalline Form V is measured at room temperature.

[0243] In a further embodiment, crystalline Form V of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.3±0.2, 9.1±0.2, 16.9±0.2, and 25.2±0.2, wherein the PXRD pattern of crystalline Form V is measured at room temperature.

[0244] In a further embodiment, crystalline Form V of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.3±0.2, 9.1±0.2, 16.9±0.2, 25.2±0.2, and 26.4±0.2, wherein the PXRD pattern of crystalline Form V is measured at room temperature.

[0245] In a further embodiment, crystalline Form V of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.3±0.2, 9.1±0.2, 16.9±0.2, 25.2±0.2, 26.4±0.2, and 27.4±0.2, wherein the PXRD pattern of crystalline Form V is measured at room temperature.

[0246] In certain embodiments, crystalline Form V of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0247] In some embodiments, crystalline Form V of Compound (I) is substantially pure. For example, crystalline Form V of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, while the remainder of the material contains other forms of the compound and / or reaction and / or process impurities.

[0248] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form V. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form V.

[0249] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form V.

[0250] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form V of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0251] In certain embodiments, the pharmaceutical composition comprises substantially pure crystalline Form V of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0252] In certain embodiments, crystalline Form V of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0253] In some embodiments, the pharmaceutical composition comprises crystalline Form V of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0254] Crystalline form W of compound (I) In some embodiments, Compound (I) is provided as a crystalline substance comprising Form W. Form W of Compound (I) is a crystalline form of a benzenesulfonic acid salt. The molar ratio of Compound (I) to benzenesulfonic acid in Form W is approximately 1:1. Form W may be a non-solvate. [Table 12]

[0255] In some embodiments, crystalline Form W of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 7.7±0.2, 9.6±0.2, 14.7±0.2, 15.6±0.2, and 25.2±0.2, wherein the PXRD pattern of crystalline Form W was measured at room temperature.

[0256] In some embodiments, crystalline Form W of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 7.7±0.2, 9.6±0.2, 14.7±0.2, 15.6±0.2, and 25.2±0.2, wherein the PXRD pattern of crystalline Form W was measured at room temperature.

[0257] In some embodiments, crystalline Form W of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 7.7±0.2, 9.6±0.2, 14.7±0.2, 15.6±0.2, and 25.2±0.2, wherein the PXRD pattern of crystalline Form W was measured at room temperature.

[0258] In certain embodiments, crystalline Form W of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.7±0.2 and 9.6±0.2, wherein the PXRD pattern of crystalline Form W is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 14.7±0.2, 15.6±0.2, and 25.2±0.2.

[0259] In certain embodiments, crystalline Form W of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.7±0.2, 9.6±0.2, and 15.6±0.2, wherein the PXRD pattern of crystalline Form W is measured at room temperature.

[0260] In certain embodiments, crystalline Form W of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.7±0.2, 9.6±0.2, and 14.7±0.2, wherein the PXRD pattern of crystalline Form W is measured at room temperature.

[0261] In a further embodiment, crystalline Form W of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.7±0.2, 9.6±0.2, 14.7±0.2, and 15.6±0.2, wherein the PXRD pattern of crystalline Form W is measured at room temperature.

[0262] In a further embodiment, crystalline Form W of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.7±0.2, 9.6±0.2, 14.7±0.2, 15.6±0.2, and 25.2±0.2, wherein the PXRD pattern of crystalline Form W was measured at room temperature.

[0263] In certain embodiments, crystalline Form W of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0264] In some embodiments, the crystalline form W of Compound (I) is characterized by an endothermic peak onset temperature in the range of approximately 176°C to 186°C. In further embodiments, the endothermic peak has an onset temperature of about 181°C. For example, in some embodiments, the crystalline form W of Compound (I) is characterized by an endothermic peak onset temperature in the range of approximately 176°C to approximately 186°C in a differential scanning calorimetry (DSC) graph. In certain embodiments, the endothermic peak onset temperature is approximately 181°C in a differential scanning calorimetry (DSC) graph. It should be understood that in some embodiments, endotherm may not be detected.

[0265] In certain embodiments, crystalline Form W of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of Form W measured at room temperature contains 2θ values ​​(°) (CuKα) of 7.7±0.2 and 9.6±0.2, and (ii) the onset temperature of the endothermic peak is about 181° C.

[0266] In certain embodiments, crystalline Form W of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form W measured at room temperature contains 2θ values ​​(°) (CuKα) of 7.7±0.2 and 9.6±0.2, and (ii) the endothermic peak has an onset temperature in the range of approximately 176° C. to 186° C. In further embodiments, the endothermic peak has an onset temperature of about 181° C.

[0267] In certain embodiments, crystalline Form W of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form W measured at room temperature contains 2θ values ​​(°) (CuKα) of 7.7±0.2, 9.6±0.2, and 14.7±0.2, and (ii) the endothermic peak has an onset temperature in the range of approximately 176° C. to 186° C. In further embodiments, the endothermic peak has an onset temperature of about 181° C.

[0268] In certain embodiments, crystalline Form W of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form W measured at room temperature contains 2θ values ​​(°) (CuKα) of 7.7±0.2, 9.6±0.2, and 15.6±0.2, and (ii) the endothermic peak has an onset temperature in the range of approximately 176° C. to 186° C. In further embodiments, the endothermic peak has an onset temperature of about 181° C.

[0269] In some embodiments, crystalline Form W of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph substantially in accordance with the graph shown in Figure 18 (bottom).

[0270] In certain embodiments, crystalline Form W of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form W measured at room temperature comprises two or more 2θ values ​​(°) (CuKα) selected from 7.7±0.2, 9.6±0.2, 14.7±0.2, 15.6±0.2, and 25.2±0.2, and (ii) the differential scanning calorimetry (DSC) graph substantially corresponds to the graph shown in FIG. 18 (bottom).

[0271] In some embodiments, the crystalline form W of Compound (I) is characterized by a mass loss of less than 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 125° C. (e.g., from room temperature). In certain embodiments, the crystalline form W of Compound (I) is characterized by a mass loss of less than 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 150° C. In certain embodiments, the crystalline form W of Compound (I) is characterized by a mass loss of less than about 1.0%, less than about 0.5%, or in further embodiments, less than about 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 150° C.

[0272] In certain embodiments, crystalline Form W of Compound (I) is substantially in accordance with the thermogravimetric analysis (TGA) graph depicted in FIG. 18 (top).

[0273] In some embodiments, crystalline Form W of Compound (I) is substantially pure. For example, crystalline Form W of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, with the remainder of the material containing other forms of the compound and / or reaction and / or process impurities.

[0274] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form W. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form W.

[0275] Also, certain embodiments provide a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form W.

[0276] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form W of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0277] In certain embodiments, the pharmaceutical composition comprises a substantially pure crystalline Form W of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0278] In certain embodiments, crystalline Form W of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0279] In some embodiments, the pharmaceutical composition comprises crystalline Form W of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0280] Crystalline Form X of Compound (I) In some embodiments, Compound (I) is provided as a crystalline substance comprising Form X. Form X of Compound (I) is a crystalline form of naphthalene-1,5-disulfonic acid salt. The molar ratio of naphthalene-1,5-disulfonic acid to Compound (I) in Form X is approximately 1:1. [Table 13]

[0281] In some embodiments, crystalline Form X of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 7.6±0.2, 10.7±0.2, 14.7±0.2, 16.2±0.2, 23.8±0.2, and 26.4±0.2, wherein the PXRD pattern of crystalline Form X is measured at room temperature.

[0282] In some embodiments, crystalline Form X of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 7.6±0.2, 10.7±0.2, 14.7±0.2, 16.2±0.2, 23.8±0.2, and 26.4±0.2, wherein the PXRD pattern of crystalline Form X is measured at room temperature.

[0283] In some embodiments, crystalline Form X of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 7.6±0.2, 10.7±0.2, 14.7±0.2, 16.2±0.2, 23.8±0.2, and 26.4±0.2, wherein the PXRD pattern of crystalline Form X is measured at room temperature.

[0284] In some embodiments, crystalline Form X of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 5 or more 2θ values ​​(°) (CuKα) selected from 7.6±0.2, 10.7±0.2, 14.7±0.2, 16.2±0.2, 23.8±0.2, and 26.4±0.2, wherein the PXRD pattern of crystalline Form X is measured at room temperature.

[0285] In certain embodiments, crystalline Form X of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.6±0.2 and 10.7±0.2, wherein the PXRD pattern of crystalline Form X is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 14.7±0.2, 16.2±0.2, 23.8±0.2, and 26.4±0.2.

[0286] In a further embodiment, crystalline Form X of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.6±0.2, 10.7±0.2, and 14.7±0.2, wherein the PXRD pattern of crystalline Form X is measured at room temperature.

[0287] In a further embodiment, crystalline Form X of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.6±0.2, 10.7±0.2, 14.7±0.2, and 16.2±0.2, wherein the PXRD pattern of crystalline Form X is measured at room temperature.

[0288] In a further embodiment, crystalline Form X of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.6±0.2, 10.7±0.2, 14.7±0.2, 16.2±0.2, and 23.8±0.2, wherein the PXRD pattern of crystalline Form X is measured at room temperature.

[0289] In certain embodiments, crystalline Form X of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.6±0.2, 10.7±0.2, 14.7±0.2, and 23.8±0.2, where the PXRD pattern of crystalline Form X is measured at room temperature.

[0290] In a further embodiment, crystalline Form X of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.6±0.2, 10.7±0.2, 14.7±0.2, 16.2±0.2, 23.8±0.2, and 26.4±0.2, wherein the PXRD pattern of crystalline Form X is measured at room temperature.

[0291] In certain embodiments, crystalline Form X of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0292] In some embodiments, crystalline Form X of Compound (I) is substantially pure. For example, crystalline Form X of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, while the remainder of the material contains other forms of the compound and / or reaction impurities and / or process impurities.

[0293] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form X. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form X.

[0294] Also, certain embodiments provide a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form X.

[0295] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form X of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0296] In certain embodiments, the pharmaceutical composition comprises substantially pure crystalline Form X of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0297] In certain embodiments, crystalline Form X of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0298] In some embodiments, the pharmaceutical composition comprises crystalline Form X of Compound (I) and other solid forms of Compound (I). The other solid forms may be, for example, other crystalline and / or amorphous solids of Compound (I).

[0299] Crystalline form Y of compound (I) In some embodiments, Compound (I) is provided as a crystalline material comprising Crystalline Form Y. Crystalline Form Y of Compound (I) is a crystalline form of the ethanesulfonic acid salt. [Table 14]

[0300] In some embodiments, crystalline Form Y of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 8.5±0.2, 9.1±0.2, 11.9±0.2, 19.7±0.2, and 24.6±0.2, wherein the PXRD pattern of crystalline Form Y is measured at room temperature.

[0301] In some embodiments, crystalline Form Y of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 8.5±0.2, 9.1±0.2, 11.9±0.2, 19.7±0.2, and 24.6±0.2, wherein the PXRD pattern of crystalline Form Y is measured at room temperature.

[0302] In some embodiments, crystalline Form Y of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 8.5±0.2, 9.1±0.2, 11.9±0.2, 19.7±0.2, and 24.6±0.2, wherein the PXRD pattern of crystalline Form Y is measured at room temperature.

[0303] In certain embodiments, crystalline Form Y of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.5±0.2 and 9.1±0.2, wherein the PXRD pattern of crystalline Form Y is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 11.9±0.2, 19.7±0.2, and 24.6±0.2.

[0304] In certain embodiments, crystalline Form Y of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.5±0.2, 9.1±0.2, and 11.9±0.2, wherein the PXRD pattern of crystalline Form Y is measured at room temperature.

[0305] In certain embodiments, crystalline Form Y of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.5±0.2, 9.1±0.2, and 19.7±0.2, wherein the PXRD pattern of crystalline Form Y is measured at room temperature.

[0306] In certain embodiments, crystalline Form Y of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 9.1±0.2, 19.7±0.2, and 24.6±0.2, wherein the PXRD pattern of crystalline Form Y is measured at room temperature.

[0307] In certain embodiments, crystalline Form Y of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.5±0.2, 9.1±0.2, 11.9±0.2, and 19.7±0.2, wherein the PXRD pattern of crystalline Form Y is measured at room temperature.

[0308] In a further embodiment, crystalline Form Y of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 8.5±0.2, 9.1±0.2, 11.9±0.2, 19.7±0.2, and 24.6±0.2, wherein the PXRD pattern of crystalline Form Y is measured at room temperature.

[0309] In certain embodiments, crystalline Form Y of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0310] In some embodiments, crystalline Form Y of Compound (I) is substantially pure. For example, crystalline Form Y of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, while the remainder of the material contains other forms of the compound and / or reaction impurities and / or process impurities.

[0311] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form Y. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form Y.

[0312] Also, certain embodiments provide a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form Y.

[0313] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form Y of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0314] In certain embodiments, the pharmaceutical composition comprises a substantially pure crystalline Form Y of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0315] In certain embodiments, crystalline Form Y of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0316] In some embodiments, the pharmaceutical composition comprises crystalline Form Y of Compound (I) and other solid forms of Compound (I). The other solid forms may be, for example, other crystalline and / or amorphous solids of Compound (I).

[0317] Crystalline form Z of compound (I) In some embodiments, Compound (I) is provided as a crystalline material comprising crystalline Form Z. Crystalline Form Z of Compound (I) is a crystalline form of the monosulfate salt trihydrate.

[0318] In certain embodiments, crystalline Form Z of Compound (I) is characterized by a unit cell parameter approximately equal to: Unit cell (triclinic): a=8.76±0.10Å b = 11.79 ± 0.10 Å c=12.68±0.10Å α=77.5±1.0° β=89.9±1.0° γ=86.5±1.0° Space group: P-1 Number of molecules per unit cell (Z): 2 Unit cell volume = 1277 ± 20 Å 3 Density (calculated value) = 1.502 g / cm 3 Here, the unit lattice constant of crystalline form Z of compound (I) was measured at a temperature of about 296K. [Table 15]

[0319] In some embodiments, crystalline Form Z of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 7.7±0.2, 15.5±0.2, 19.0±0.2, and 20.0±0.2, wherein the PXRD pattern of crystalline Form Z is measured at room temperature.

[0320] In some embodiments, crystalline Form Z of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 7.7±0.2, 15.5±0.2, 19.0±0.2, and 20.0±0.2, wherein the PXRD pattern of crystalline Form Z is measured at room temperature.

[0321] In certain embodiments, crystalline Form Z of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.7±0.2 and 15.5±0.2. The PXRD pattern of crystalline Form Z is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 19.0±0.2 and 20.0±0.2.

[0322] In certain embodiments, crystalline Form Z of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.7±0.2, 15.5±0.2, and 19.0±0.2, wherein the PXRD pattern of crystalline Form Z is measured at room temperature.

[0323] In certain embodiments, crystalline Form Z of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.7±0.2, 15.5±0.2, and 20.0±0.2, wherein the PXRD pattern of crystalline Form Z is measured at room temperature.

[0324] In certain embodiments, crystalline Form Z of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.7±0.2, 19.0±0.2, and 20.0±0.2, wherein the PXRD pattern of crystalline Form Z is measured at room temperature.

[0325] In certain embodiments, crystalline Form Z of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.7±0.2, 15.5±0.2, 19.0±0.2, and 20.0±0.2, wherein the PXRD pattern of crystalline Form Z is measured at room temperature.

[0326] In certain embodiments, crystalline Form Z of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0327] In some embodiments, crystalline Form Z of Compound (I) is substantially pure. For example, crystalline Form Z of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, with the remainder of the material containing other forms of the compound and / or reaction impurities and / or process impurities.

[0328] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form Z. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form Z.

[0329] Also, certain embodiments provide a composition comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form Z.

[0330] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form Z of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0331] In certain embodiments, the pharmaceutical composition comprises a substantially pure crystalline Form Z of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0332] In certain embodiments, crystalline Form Z of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0333] In some embodiments, the pharmaceutical composition comprises crystalline Form Z of Compound (I) and other solid forms of Compound (I). The other solid forms may be, for example, other crystalline and / or amorphous solids of Compound (I).

[0334] Crystalline Form AA of Compound (I) In some embodiments, Compound (I) is provided as a crystalline material comprising crystalline Form AA. Crystalline Form AA of Compound (I) is a crystalline form of the sulfate salt. [Table 16]

[0335] In some embodiments, crystalline Form AA of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 6.3±0.2, 7.7±0.2, 8.2±0.2, 11.6±0.2, and 25.4±0.2, wherein the PXRD pattern of crystalline Form AA was measured at room temperature.

[0336] In some embodiments, crystalline Form AA of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 6.3±0.2, 7.7±0.2, 8.2±0.2, 11.6±0.2, and 25.4±0.2, wherein the PXRD pattern of crystalline Form AA was measured at room temperature.

[0337] In some embodiments, crystalline Form AA of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 6.3±0.2, 7.7±0.2, 8.2±0.2, 11.6±0.2, and 25.4±0.2, wherein the PXRD pattern of crystalline Form AA was measured at room temperature.

[0338] In certain embodiments, crystalline Form AA of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.3±0.2 and 7.7±0.2. The PXRD pattern of crystalline Form AA is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 8.2±0.2, 11.6±0.2, and 25.4±0.2.

[0339] In certain embodiments, crystalline Form AA of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.3±0.2, 7.7±0.2, and 8.2±0.2, where the PXRD pattern of crystalline Form AA is measured at room temperature.

[0340] In certain embodiments, crystalline Form AA of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.7±0.2 and 8.2±0.2. The PXRD pattern of crystalline Form AA is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 6.3±0.2, 11.6±0.2, and 25.4±0.2.

[0341] In certain embodiments, crystalline Form AA of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.3±0.2, 7.7±0.2, 8.2±0.2, and 11.6±0.2, where the PXRD pattern of crystalline Form AA is measured at room temperature.

[0342] In a further embodiment, crystalline Form AA of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.3±0.2, 7.7±0.2, 8.2±0.2, 11.6±0.2, and 25.4±0.2, wherein the PXRD pattern of crystalline Form AA was measured at room temperature.

[0343] In certain embodiments, crystalline Form AA of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0344] In certain embodiments, the crystalline form AA of Compound (I) is characterized by having a maximum endothermic peak in the range of approximately 189°C to 199°C. In further embodiments, the maximum endothermic peak is about 194°C. For example, in some embodiments, the crystalline form AA of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph having a maximum endothermic peak in the range of about 189°C to about 199°C. In certain embodiments, the differential scanning calorimetry (DSC) graph has an endothermic maximum of about 194°C. It should be understood that in some embodiments, endothermic heat may not be detected.

[0345] In certain embodiments, crystalline Form AA of Compound (I) is characterized by (i) a powder X-ray diffraction (PXRD) pattern of crystalline Form AA measured at room temperature comprising 2θ values ​​(°) (CuKα) of 6.3±0.2 and 7.7±0.2, and (ii) a maximum endothermic peak in the range of approximately 189° C. to 199° C. In further embodiments, the maximum endothermic peak is about 194° C.

[0346] In certain embodiments, crystalline Form AA of Compound (I) is characterized by (i) a powder X-ray diffraction (PXRD) pattern of crystalline Form AA measured at room temperature comprising 2θ values ​​(°) (CuKα) of 7.7±0.2 and 8.2±0.2, and (ii) a maximum endothermic peak in the range of approximately 189° C. to 199° C. In further embodiments, the maximum endothermic peak is about 194° C.

[0347] In certain embodiments, crystalline Form AA of Compound (I) is characterized by (i) a powder X-ray diffraction (PXRD) pattern of crystalline Form AA measured at room temperature comprising 2θ values ​​(°) (CuKα) of 7.7±0.2, 8.2±0.2, and 11.6±0.2, and (ii) a maximum endothermic peak in the range of approximately 189° C. to 199° C. In further embodiments, the maximum endothermic peak is about 194° C.

[0348] In certain embodiments, crystalline Form AA of Compound (I) is characterized by (i) a powder X-ray diffraction (PXRD) pattern of crystalline Form AA measured at room temperature comprising 2θ values ​​(°) (CuKα) of 6.3±0.2, 7.7±0.2, and 8.2±0.2, and (ii) a maximum endothermic peak in the range of approximately 189° C. to 199° C. In further embodiments, the maximum endothermic peak is about 194° C.

[0349] In some embodiments, crystalline Form AA of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph substantially in accordance with the graph shown in FIG.

[0350] In certain embodiments, crystalline Form AA of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form AA measured at room temperature comprises two or more 2θ values ​​(°) (CuKα) selected from 6.3±0.2, 7.7±0.2, 8.2±0.2, 11.6±0.2, and 25.4±0.2, and (ii) the differential scanning calorimetry (DSC) graph substantially corresponds to the graph depicted in FIG. 23.

[0351] In some embodiments, crystalline Form AA of Compound (I) is substantially pure. For example, crystalline Form AA of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, while the remainder of the material contains other forms of the compound and / or reaction impurities and / or process impurities.

[0352] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form AA. In such embodiments, the crystalline form of Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, more preferably at least about 99% by weight of crystalline Form AA.

[0353] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is crystalline Form AA.

[0354] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form AA of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0355] In certain embodiments, the pharmaceutical composition comprises substantially pure crystalline Form AA of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0356] In certain embodiments, crystalline Form AA of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0357] In some embodiments, the pharmaceutical composition comprises crystalline Form AA of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0358] Crystalline form AB of compound (I) In some embodiments, Compound (I) is provided as a crystalline material comprising crystalline Form AB. Crystalline Form AB of Compound (I) is a crystalline form of the sulfate salt. Crystalline Form AB may be a non-solvate. [Table 17]

[0359] In some embodiments, crystalline Form AB of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 7.8±0.2, 9.7±0.2, 10.3±0.2, 11.4±0.2, and 23.8±0.2, wherein the PXRD pattern of crystalline Form AB was measured at room temperature.

[0360] In some embodiments, crystalline Form AB of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 7.8±0.2, 9.7±0.2, 10.3±0.2, 11.4±0.2, and 23.8±0.2, wherein the PXRD pattern of crystalline Form AB was measured at room temperature.

[0361] In some embodiments, crystalline Form AB of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 7.8±0.2, 9.7±0.2, 10.3±0.2, 11.4±0.2, and 23.8±0.2, wherein the PXRD pattern of crystalline Form AB was measured at room temperature.

[0362] In certain embodiments, crystalline Form AB of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.8±0.2 and 9.7±0.2. The PXRD pattern of crystalline Form AB is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 10.3±0.2, 11.4±0.2, and 23.8±0.2.

[0363] In certain embodiments, crystalline Form AB of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.8±0.2, 9.7±0.2, and 23.8±0.2, wherein the PXRD pattern of crystalline Form AB was measured at room temperature.

[0364] In certain embodiments, crystalline Form AB of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.8±0.2, 9.7±0.2, and 10.3±0.2, wherein the PXRD pattern of crystalline Form AB was measured at room temperature.

[0365] In a further embodiment, crystalline Form AB of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.8±0.2, 9.7±0.2, 10.3±0.2, and 11.4±0.2, wherein the PXRD pattern of crystalline Form AB was measured at room temperature.

[0366] In a further embodiment, crystalline Form AB of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.8±0.2, 9.7±0.2, 10.3±0.2, 11.4±0.2, and 23.8±0.2, wherein the PXRD pattern of crystalline Form AB was measured at room temperature.

[0367] In certain embodiments, crystalline Form AB of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0368] In certain embodiments, crystalline form AB of Compound (I) is characterized by having a maximum endothermic peak in the range of approximately 217°C to 227°C. In further embodiments, the maximum endothermic peak is about 222°C. For example, in some embodiments, crystalline form AB of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph having a maximum endothermic peak in the range of about 217°C to about 227°C. In certain embodiments, the differential scanning calorimetry (DSC) graph has an endothermic maximum of about 222°C. It should be understood that in some embodiments, endothermic heat may not be detected.

[0369] In certain embodiments, crystalline Form AB of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form AB measured at room temperature contains 2θ values ​​(°) (CuKα) of 7.8±0.2 and 9.7±0.2, and (ii) the maximum endothermic peak is in the range of approximately 217° C. to 227° C. In further embodiments, the maximum endothermic peak is about 222° C.

[0370] In certain embodiments, crystalline Form AB of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form AB measured at room temperature contains 2θ values ​​(°) (CuKα) of 7.8±0.2, 9.7±0.2, and 10.3±0.2, and (ii) the maximum endothermic peak is in the range of approximately 217° C. to 227° C. In further embodiments, the maximum endothermic peak is about 222° C.

[0371] In certain embodiments, crystalline Form AB of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form AB measured at room temperature contains 2θ values ​​(°) (CuKα) of 7.8±0.2, 9.7±0.2, and 23.8±0.2, and (ii) the maximum endothermic peak is in the range of approximately 217° C. to 227° C. In further embodiments, the maximum endothermic peak is about 222° C.

[0372] In some embodiments, crystalline Form AB of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph substantially in accordance with the graph shown in FIG.

[0373] In certain embodiments, crystalline Form AB of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form AB, measured at room temperature, comprises two or more 2θ values ​​(°) (CuKα) selected from 7.8±0.2, 9.7±0.2, 10.3±0.2, 11.4±0.2, and 23.8±0.2, and (ii) the differential scanning calorimetry (DSC) graph substantially corresponds to the graph depicted in FIG. 25.

[0374] In some embodiments, crystalline form AB of Compound (I) is characterized by a mass loss of less than 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 100° C. (e.g., from room temperature). In certain embodiments, crystalline form AB of Compound (I) is characterized by a mass loss of less than 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 120° C. In certain embodiments, crystalline form AB of Compound (I) is characterized by a mass loss of less than about 1.0%, less than about 0.5%, or in further embodiments, less than about 0.1% in a thermogravimetric analysis (TGA) graph when heated to a temperature of about 120° C.

[0375] In certain embodiments, crystalline Form AB of Compound (I) substantially conforms to the thermogravimetric analysis (TGA) graph depicted in FIG.

[0376] In some embodiments, crystalline Form AB of Compound (I) is substantially pure. For example, crystalline Form AB of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, with the remainder of the material containing other forms of the compound and / or reaction impurities and / or process impurities.

[0377] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form AB. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form AB.

[0378] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is crystalline Form AB.

[0379] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form AB of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0380] In certain embodiments, the pharmaceutical composition comprises substantially pure crystalline Form AB of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0381] In certain embodiments, crystalline Form AB of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0382] In some embodiments, the pharmaceutical composition comprises crystalline Form AB of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0383] Crystalline form AC of compound (I) In some embodiments, Compound (I) is provided as a crystalline material, including crystalline Form AC. Crystalline Form AC of Compound (I) is a crystalline form of the monohydrochloride salt, trihydrate.

[0384] In certain embodiments, crystalline Form AC of Compound (I) is characterized by a unit cell parameter approximately equal to: Unit cell (triclinic): a=8.76±0.10Å b = 11.75 ± 0.10 Å c=12.31±0.10Å α=105.5±1.0° β=96.3±1.0° γ=95.0±1.0° Space group: P-1 Number of molecules per unit cell (Z): 2 Unit cell volume = 1205 ± 20 Å 3 Density (calculated value) = 1.422 g / cm 3 Here, the unit lattice constant of crystalline form AC of compound (I) was measured at a temperature of about 296K. [Table 18]

[0385] In some embodiments, crystalline Form AC of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 7.6±0.2, 10.2±0.2, 13.7±0.2, 20.4±0.2, and 25.9±0.2, wherein the PXRD pattern of crystalline Form AC was measured at room temperature.

[0386] In some embodiments, crystalline Form AC of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 7.6±0.2, 10.2±0.2, 13.7±0.2, 20.4±0.2, and 25.9±0.2, wherein the PXRD pattern of crystalline Form AC was measured at room temperature.

[0387] In some embodiments, crystalline Form AC of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 7.6±0.2, 10.2±0.2, 13.7±0.2, 20.4±0.2, and 25.9±0.2, wherein the PXRD pattern of crystalline Form AC was measured at room temperature.

[0388] In certain embodiments, crystalline Form AC of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.6±0.2 and 10.2±0.2. Wherein the PXRD pattern of crystalline Form AC is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 13.7±0.2, 20.4±0.2, and 25.9±0.2.

[0389] In certain embodiments, crystalline Form AC of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.6±0.2 and 13.7±0.2. Wherein the PXRD pattern of crystalline Form AC is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 10.2±0.2, 20.4±0.2, and 25.9±0.2.

[0390] In certain embodiments, crystalline Form AC of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.6±0.2 and 25.9±0.2. Wherein the PXRD pattern of crystalline Form AC is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 10.2±0.2, 13.7±0.2, and 20.4±0.2.

[0391] In certain embodiments, crystalline Form AC of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.6±0.2, 10.2±0.2, and 13.7±0.2, wherein the PXRD pattern of crystalline Form AC is measured at room temperature.

[0392] In a further embodiment, crystalline Form AC of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.6±0.2, 10.2±0.2, 13.7±0.2, and 20.4±0.2, wherein the PXRD pattern of crystalline Form AC was measured at room temperature.

[0393] In a further embodiment, crystalline Form AC of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.6±0.2, 10.2±0.2, 13.7±0.2, 20.4±0.2, and 25.9±0.2, wherein the PXRD pattern of crystalline Form AC was measured at room temperature.

[0394] In certain embodiments, crystalline Form AC of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0395] In some embodiments, crystalline Form AC of Compound (I) is substantially pure. For example, crystalline Form AC of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, with the remainder of the material containing other forms of the compound and / or reaction and / or process impurities.

[0396] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form AC. In such embodiments, the crystalline form of Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, more preferably at least about 99% by weight of crystalline Form AC.

[0397] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form AC.

[0398] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form AC of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0399] In certain embodiments, the pharmaceutical composition comprises substantially pure crystalline Form AC of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0400] In certain embodiments, crystalline Form AC of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0401] In some embodiments, the pharmaceutical composition comprises crystalline Form AC of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0402] Crystalline form AD of compound (I) In some embodiments, Compound (I) is provided as a crystalline material, including crystalline Form AD. Crystalline Form AD of Compound (I) is a crystalline form of the mesylate salt. [Table 19]

[0403] In some embodiments, crystalline Form AD of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 6.0±0.2, 6.9±0.2, 7.8±0.2, 10.3±0.2, and 13.8±0.2, wherein the PXRD pattern of crystalline Form AD was measured at room temperature.

[0404] In some embodiments, crystalline Form AD of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 6.0±0.2, 6.9±0.2, 7.8±0.2, 10.3±0.2, and 13.8±0.2, wherein the PXRD pattern of crystalline Form AD was measured at room temperature.

[0405] In some embodiments, crystalline Form AD of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 6.0±0.2, 6.9±0.2, 7.8±0.2, 10.3±0.2, and 13.8±0.2, wherein the PXRD pattern of crystalline Form AD was measured at room temperature.

[0406] In certain embodiments, crystalline Form AD of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.0±0.2 and 6.9±0.2. The PXRD pattern of crystalline Form AD is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 7.8±0.2, 10.3±0.2, and 13.8±0.2.

[0407] In certain embodiments, crystalline Form AD of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.0±0.2, 6.9±0.2, and 10.3±0.2, wherein the PXRD pattern of crystalline Form AD was measured at room temperature.

[0408] In a further embodiment, crystalline Form AD of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.0±0.2, 6.9±0.2, 10.3±0.2, and 13.8±0.2, wherein the PXRD pattern of crystalline Form AD was measured at room temperature.

[0409] In certain embodiments, crystalline Form AD of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.0±0.2, 6.9±0.2, and 7.8±0.2, wherein the PXRD pattern of crystalline Form AD is measured at room temperature.

[0410] In a further embodiment, crystalline Form AD of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.0±0.2, 6.9±0.2, 7.8±0.2, and 10.3±0.2, wherein the PXRD pattern of crystalline Form AD was measured at room temperature.

[0411] In a further embodiment, crystalline Form AD of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 6.0±0.2, 6.9±0.2, 7.8±0.2, 10.3±0.2, and 13.8±0.2, wherein the PXRD pattern of crystalline Form AD was measured at room temperature.

[0412] In certain embodiments, crystalline Form AD of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0413] In some embodiments, crystalline Form AD of Compound (I) is substantially pure. For example, crystalline Form AD of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, with the remainder of the material containing other forms of the compound and / or reaction and / or process impurities.

[0414] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form AD. In such embodiments, the crystalline form of Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, more preferably at least about 99% by weight of crystalline Form AD.

[0415] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is crystalline Form AD.

[0416] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form AD of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0417] In certain embodiments, the pharmaceutical composition comprises substantially pure crystalline Form AD of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0418] In certain embodiments, crystalline Form AD of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0419] In some embodiments, the pharmaceutical compositions comprise crystalline Form AD of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0420] Crystalline form AE of compound (I) In some embodiments, Compound (I) is provided as a crystalline material comprising crystalline Form AE. Crystalline Form AE of Compound (I) is a crystalline form of the phosphate salt. [Table 20]

[0421] In some embodiments, crystalline Form AE of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 4.8±0.2, 6.2±0.2, 7.3±0.2, 9.6±0.2, and 12.5±0.2, wherein the PXRD pattern of crystalline Form AE was measured at room temperature.

[0422] In some embodiments, crystalline Form AE of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 4.8±0.2, 6.2±0.2, 7.3±0.2, 9.6±0.2, and 12.5±0.2, wherein the PXRD pattern of crystalline Form AE was measured at room temperature.

[0423] In some embodiments, crystalline Form AE of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 4.8±0.2, 6.2±0.2, 7.3±0.2, 9.6±0.2, and 12.5±0.2, wherein the PXRD pattern of crystalline Form AE was measured at room temperature.

[0424] In certain embodiments, crystalline Form AE of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 4.8±0.2 and 6.2±0.2. Wherein the PXRD pattern of crystalline Form AE is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 7.3±0.2, 9.6±0.2, and 12.5±0.2.

[0425] In certain embodiments, crystalline Form AE of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 4.8±0.2 and 9.6±0.2. Wherein, the PXRD pattern of crystalline Form AE is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 6.2±0.2, 7.3±0.2, and 12.5±0.2. For example, in some embodiments, crystalline Form AE of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 4.8±0.2, 6.2±0.2, and 9.6±0.2. Wherein, the PXRD pattern of crystalline Form AE is measured at room temperature.

[0426] In certain embodiments, crystalline Form AE of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 4.8±0.2, 6.2±0.2, and 7.3±0.2, wherein the PXRD pattern of crystalline Form AE is measured at room temperature.

[0427] In a further embodiment, crystalline Form AE of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 4.8±0.2, 6.2±0.2, 7.3±0.2, and 9.6±0.2, wherein the PXRD pattern of crystalline Form AE was measured at room temperature.

[0428] In further embodiments, crystalline Form AE of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 4.8±0.2, 6.2±0.2, 7.3±0.2, 9.6±0.2, and 12.5±0.2, wherein the PXRD pattern of crystalline Form AE was measured at room temperature.

[0429] In certain embodiments, crystalline Form AE of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0430] In certain embodiments, the crystalline Form AE of Compound (I) is characterized by a maximum endothermic peak in the range of approximately 186°C to 196°C. In further embodiments, the maximum endotherm is about 191°C. For example, in some embodiments, the crystalline Form AE of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph having a maximum endothermic peak in the range of about 186°C to about 196°C. In certain embodiments, the differential scanning calorimetry (DSC) graph has an endothermic maximum of about 191°C. It should be understood that in some embodiments, no endotherm may be detected.

[0431] In certain embodiments, crystalline Form AE of Compound (I) is characterized by (i) a powder X-ray diffraction (PXRD) pattern of crystalline Form AE measured at room temperature comprising 2θ values ​​(°) (CuKα) of 4.8±0.2 and 6.2±0.2, and (ii) a maximum endothermic peak in the range of approximately 186° C. to 196° C. In further embodiments, the maximum endothermic peak is about 191° C.

[0432] In certain embodiments, crystalline Form AE of Compound (I) (i) comprises 2θ values ​​(°) (CuKα) of 4.8±0.2 and 9.6±0.2 in the powder X-ray diffraction (PXRD) pattern of crystalline Form AE measured at room temperature, and (ii) has a maximum endothermic peak in the range of approximately 186° C. to 196° C. In further embodiments, the maximum endothermic peak is characterized by being about 191° C.

[0433] In certain embodiments, crystalline Form AE of Compound (I) (i) comprises 2θ values ​​(°) (CuKα) of 4.8±0.2, 6.2±0.2, and 7.3±0.2 in a powder X-ray diffraction (PXRD) pattern of crystalline Form AE measured at room temperature, and (ii) has a maximum endothermic peak in the range of approximately 186° C. to 196° C. In further embodiments, the maximum endothermic peak is characterized by being about 191° C.

[0434] In some embodiments, crystalline Form AE of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph substantially in accordance with the graph depicted in FIG.

[0435] In certain embodiments, crystalline Form AE of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form AE, measured at room temperature, comprises two or more 2θ values ​​(°) (CuKα) selected from 4.8±0.2, 6.2±0.2, 7.3±0.2, 9.6±0.2, and 12.5±0.2, and (ii) the differential scanning calorimetry (DSC) graph substantially corresponds to the graph depicted in FIG. 30.

[0436] In some embodiments, crystalline Form AE of Compound (I) is substantially pure. For example, crystalline Form AE of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, with the remainder of the material containing other forms of the compound and / or reaction and / or process impurities.

[0437] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form AE. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight of crystalline Form AE.

[0438] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form AE.

[0439] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form AE of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0440] In certain embodiments, the pharmaceutical composition comprises substantially pure crystalline Form AE of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0441] In certain embodiments, crystalline Form AE of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0442] In some embodiments, the pharmaceutical compositions comprise crystalline Form AE of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0443] Crystalline form AF of compound (I) In some embodiments, Compound (I) is provided as a crystalline material, including crystalline Form AF, which is a crystalline form of a hydrochloride (HCl) solvate, where the solvate includes ethanol, or further includes ethanol and water. [Table 21]

[0444] In some embodiments, crystalline Form AF of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 7.4±0.2, 13.7±0.2, 18.2±0.2, 20.5±0.2, 21.3±0.2, 22.5±0.2, 23.8±0.2, and 26.2±0.2, wherein the PXRD pattern of crystalline Form AF was measured at room temperature.

[0445] In some embodiments, crystalline Form AF of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 7.4±0.2, 13.7±0.2, 18.2±0.2, 20.5±0.2, 21.3±0.2, 22.5±0.2, 23.8±0.2, and 26.2±0.2, wherein the PXRD pattern of crystalline Form AF was measured at room temperature.

[0446] In some embodiments, crystalline Form AF of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 7.4±0.2, 13.7±0.2, 18.2±0.2, 20.5±0.2, 21.3±0.2, 22.5±0.2, 23.8±0.2, and 26.2±0.2, wherein the PXRD pattern of crystalline Form AF was measured at room temperature.

[0447] In some embodiments, crystalline Form AF of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 5 or more 2θ values ​​(°) (CuKα) selected from 7.4±0.2, 13.7±0.2, 18.2±0.2, 20.5±0.2, 21.3±0.2, 22.5±0.2, 23.8±0.2, and 26.2±0.2, wherein the PXRD pattern of crystalline Form AF was measured at room temperature.

[0448] In certain embodiments, crystalline Form AF of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.4±0.2 and 13.7±0.2. The PXRD pattern of crystalline Form AF is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 18.2±0.2, 20.5±0.2, 21.3±0.2, 22.5±0.2, 23.8±0.2, and 26.2±0.2.

[0449] In certain embodiments, crystalline Form AF of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.4±0.2, 13.7±0.2, and 26.2±0.2, wherein the PXRD pattern of crystalline Form AF was measured at room temperature.

[0450] In certain embodiments, crystalline Form AF of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.4±0.2, 13.7±0.2, and 18.2±0.2, wherein the PXRD pattern of crystalline Form AF was measured at room temperature.

[0451] In certain embodiments, crystalline Form AF of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.4±0.2, 13.7±0.2, and 23.8±0.2, wherein the PXRD pattern of crystalline Form AF was measured at room temperature.

[0452] In a further embodiment, crystalline Form AF of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.4±0.2, 13.7±0.2, 18.2±0.2, and 23.8±0.2, wherein the PXRD pattern of crystalline Form AF was measured at room temperature.

[0453] In a further embodiment, crystalline Form AF of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.4±0.2, 13.7±0.2, 18.2±0.2, 23.8±0.2, and 26.2±0.2, wherein the PXRD pattern of crystalline Form AF was measured at room temperature.

[0454] In a further embodiment, crystalline Form AF of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.4±0.2, 13.7±0.2, 18.2±0.2, 20.5±0.2, 21.3±0.2, 22.5±0.2, 23.8±0.2, and 26.2±0.2, wherein the PXRD pattern of crystalline Form AF was measured at room temperature.

[0455] In certain embodiments, crystalline Form AF of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0456] In some embodiments, the crystalline form AF of Compound (I) is characterized by a broad endotherm in the range of approximately 95°C to 105°C. In certain embodiments, the broad endotherm is about 100°C. In certain embodiments, the crystalline form AF of Compound (I) is characterized by a maximum endotherm peak in the range of approximately 232°C to 242°C. In further embodiments, the maximum endotherm is about 237°C. For example, in some embodiments, the crystalline form AF of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph having a maximum endotherm peak in the range of approximately 232°C to approximately 242°C. In certain embodiments, the differential scanning calorimetry (DSC) graph has an endotherm maximum of approximately 237°C. In further embodiments, the differential scanning calorimetry (DSC) graph also has a broad endotherm of approximately 100°C. It should be understood that in some embodiments, one or more endotherms may not be detected.

[0457] In certain embodiments, crystalline Form AF of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form AF, measured at room temperature, comprises 2θ values ​​(°) (CuKα) of 7.4±0.2 and 13.7±0.2, and (ii) the maximum endothermic peak is in the range of approximately 232° C. to 242° C. In further embodiments, the maximum endothermic peak is about 237° C.

[0458] In certain embodiments, crystalline Form AF of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form AF, measured at room temperature, contains 2θ values ​​(°) (CuKα) of 7.4±0.2, 13.7±0.2, and 18.2±0.2, and (ii) has a maximum endothermic peak in the range of approximately 232° C. to 242° C. In further embodiments, the maximum endothermic peak is about 237° C.

[0459] In certain embodiments, crystalline Form AF of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form AF, measured at room temperature, contains 2θ values ​​(°) (CuKα) of 7.4±0.2, 13.7±0.2, and 23.8±0.2, and (ii) has a maximum endothermic peak in the range of approximately 232° C. to 242° C. In further embodiments, the maximum endothermic peak is about 237° C.

[0460] In the above embodiments describing an endotherm, Crystalline Form AF of Compound (I) is further characterized by a broad endotherm in the range of approximately 95° C. to 105° C. In further embodiments, the endotherm is about 100° C.

[0461] In some embodiments, crystalline Form AF of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph substantially in accordance with the graph shown in FIG.

[0462] In certain embodiments, crystalline Form AF of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form AF, measured at room temperature, comprises two or more 2θ values ​​(°) (CuKα) selected from 7.4±0.2, 13.7±0.2, 18.2±0.2, 20.5±0.2, 21.3±0.2, 22.5±0.2, 23.8±0.2, and 26.2±0.2, and (ii) the differential scanning calorimetry (DSC) graph substantially corresponds to the graph depicted in FIG. 32.

[0463] In some embodiments, crystalline Form AF of Compound (I) is characterized by a thermogravimetric analysis (TGA) mass loss of about 10% or less upon heating (e.g., from room temperature) to about 100° C. In certain embodiments, crystalline Form AF of Compound (I) is characterized by a thermogravimetric analysis (TGA) mass loss of about 10% upon heating (e.g., from room temperature) to about 105° C.

[0464] In certain embodiments, crystalline Forms AF of Compound (I) are substantially in accordance with the thermogravimetric analysis (TGA) graph depicted in FIG.

[0465] In some embodiments, crystalline Form AF of Compound (I) is substantially pure. For example, crystalline Form AF of Compound (I) may be a sample that is 90% or more, 95% or more, or 99% or more by weight pure, with the remainder of the material containing other forms of the compound and / or reaction and / or process impurities.

[0466] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form AF. In such embodiments, the crystalline Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight, of crystalline Form AF.

[0467] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form AF.

[0468] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form AF of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0469] In certain embodiments, the pharmaceutical composition comprises substantially pure crystalline Form AF of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0470] In certain embodiments, crystalline Form AF of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0471] In some embodiments, the pharmaceutical compositions comprise crystalline Form AF of Compound (I) and other solid forms of Compound (I). The other solid forms can be, for example, other crystalline and / or amorphous solids of Compound (I).

[0472] Crystalline form AG of compound (I) In some embodiments, Compound (I) is provided as a crystalline material comprising crystalline Form AG. Crystalline Form AG of Compound (I) is a crystalline form of a solvate of the hydrochloride salt (HCl), where the solvate includes acetic acid. [Table 22]

[0473] In some embodiments, crystalline Form AG of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 7.2±0.2, 13.8±0.2, 18.5±0.2, 21.8±0.2, 24.2±0.2, 25.3±0.2, and 26.8±0.2, wherein the PXRD pattern of crystalline Form AG was measured at room temperature.

[0474] In some embodiments, crystalline Form AG of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising three or more 2θ values ​​(°) (CuKα) selected from 7.2±0.2, 13.8±0.2, 18.5±0.2, 21.8±0.2, 24.2±0.2, 25.3±0.2, and 26.8±0.2, wherein the PXRD pattern of crystalline Form AG was measured at room temperature.

[0475] In some embodiments, crystalline Form AG of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 4 or more 2θ values ​​(°) (CuKα) selected from 7.2±0.2, 13.8±0.2, 18.5±0.2, 21.8±0.2, 24.2±0.2, 25.3±0.2, and 26.8±0.2, wherein the PXRD pattern of crystalline Form AG was measured at room temperature.

[0476] In some embodiments, crystalline Form AG of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 5 or more 2θ values ​​(°) (CuKα) selected from 7.2±0.2, 13.8±0.2, 18.5±0.2, 21.8±0.2, 24.2±0.2, 25.3±0.2, and 26.8±0.2, wherein the PXRD pattern of crystalline Form AG was measured at room temperature.

[0477] In certain embodiments, crystalline form AG of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.2±0.2 and 13.8±0.2. Wherein, the PXRD pattern of crystalline form AG is measured at room temperature. In further embodiments, the PXRD pattern further comprises one or more 2θ values ​​(°) selected from 18.5±0.2, 21.8±0.2, 24.2±0.2, 25.3±0.2, and 26.8±0.2. For example, in certain embodiments, the PXRD pattern measured at room temperature comprises 2θ values ​​(°) (CuKα) of 7.2±0.2, 13.8±0.2, and 25.3±0.2.

[0478] In certain embodiments, crystalline Form AG of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.2±0.2, 13.8±0.2, and 18.5±0.2, wherein the PXRD pattern of crystalline Form AG is measured at room temperature.

[0479] In a further embodiment, crystalline Form AG of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.2±0.2, 13.8±0.2, 18.5±0.2, and 21.8±0.2, wherein the PXRD pattern of crystalline Form AG was measured at room temperature.

[0480] In a further embodiment, crystalline Form AG of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.2±0.2, 13.8±0.2, 18.5±0.2, 21.8±0.2, and 24.2±0.2, wherein the PXRD pattern of crystalline Form AG was measured at room temperature.

[0481] In a further embodiment, crystalline Form AG of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.2±0.2, 13.8±0.2, 18.5±0.2, 21.8±0.2, 24.2±0.2, and 25.3±0.2, wherein the PXRD pattern of crystalline Form AG was measured at room temperature.

[0482] In a further embodiment, crystalline Form AG of Compound (I) is characterized by a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 7.2±0.2, 13.8±0.2, 18.5±0.2, 21.8±0.2, 24.2±0.2, 25.3±0.2, and 26.8±0.2, wherein the PXRD pattern of crystalline Form AG was measured at room temperature.

[0483] In certain embodiments, crystalline Form AG of Compound (I) is characterized by an observed powder X-ray diffraction pattern (CuKα, measured at room temperature) substantially as shown in FIG.

[0484] In some embodiments, the crystalline form AG of Compound (I) is characterized by having a maximum endothermic peak in the range of about 146°C to about 156°C. In certain embodiments, the maximum endothermic is about 151°C. For example, in some embodiments, the crystalline form AG of Compound (I) is characterized by having a maximum endothermic peak in the range of about 146°C to about 156°C in the graph of differential scanning calorimetry (DSC). In certain embodiments, the maximum endothermic is about 151°C in the graph of differential scanning calorimetry (DSC). In certain embodiments, the crystalline form AG of Compound (I) is characterized by having a maximum endothermic peak in the range of about 231°C to 241°C. In certain embodiments, the maximum endothermic is about 236°C. For example, in some embodiments, the crystalline form AG of Compound (I) is characterized by having a maximum endothermic peak in the range of about 231°C to about 241°C in the graph of differential scanning calorimetry (DSC). In certain embodiments, the differential scanning calorimetry (DSC) graph shows an endothermic maximum of about 236° C. In certain embodiments, Compound (I) crystalline Form AG is characterized by a differential scanning calorimetry (DSC) graph showing both endotherms as described above. It should be understood that in some embodiments, one or more endotherms may not be detected.

[0485] In certain embodiments, crystalline Form AG of Compound (I) is characterized by (i) a powder X-ray diffraction (PXRD) pattern of crystalline Form AG measured at room temperature containing 2θ values ​​(°) (CuKα) of 7.2±0.2 and 13.8±0.2, and (ii) a maximum endothermic peak in the range of approximately 231°C to 241°C. In further embodiments, the maximum endothermic peak is about 236°C. In some embodiments, crystalline Form AG of Compound (I) is further characterized by a maximum endothermic peak in the range of approximately 146°C to 156°C. In further embodiments, the maximum endothermic peak is about 151°C.

[0486] In certain embodiments, crystalline Form AG of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form AG measured at room temperature contains 2θ values ​​(°) (CuKα) of 7.2±0.2, 13.8±0.2, and 18.5±0.2, and (ii) the maximum endothermic peak is approximately in the range of 146°C to 156°C, and one or more maximum endothermic peaks are approximately in the range of 231°C to 241°C.

[0487] In some embodiments, crystalline Form AG of Compound (I) is characterized by a differential scanning calorimetry (DSC) graph substantially in accordance with the graph depicted in FIG.

[0488] In certain embodiments, crystalline Form AG of Compound (I) is characterized in that (i) the powder X-ray diffraction (PXRD) pattern of crystalline Form AG measured at room temperature comprises two or more 2θ values ​​(°) (CuKα) selected from 7.2±0.2, 13.8±0.2, 18.5±0.2, 21.8±0.2, 24.2±0.2, 25.3±0.2, and 26.8±0.2, and (ii) the differential scanning calorimetry (DSC) graph substantially corresponds to the graph depicted in FIG. 35.

[0489] In some embodiments, crystalline Form AG of Compound (I) is characterized by a thermogravimetric analysis (TGA) mass loss of about 10% or less upon heating (e.g., from room temperature) to about 100° C. In certain embodiments, crystalline Form AG of Compound (I) is characterized by a thermogravimetric analysis (TGA) mass loss of about 11% upon heating (e.g., from room temperature) to about 160° C.

[0490] In certain embodiments, crystalline Form AG of Compound (I) substantially conforms to the thermogravimetric analysis (TGA) graph depicted in FIG.

[0491] In some embodiments, the crystalline form AG of Compound (I) is substantially pure. For example, the crystalline form AG of Compound (I) may be a sample that is 90% or more by weight, 95% or more by weight, or 99% or more by weight pure, while the remaining material contains other forms of the compound and / or reaction impurities and / or process impurities.

[0492] In certain embodiments, the crystalline form of Compound (I) essentially comprises crystalline Form AG. In such embodiments, the crystalline form of Compound (I) may comprise at least about 90% by weight, preferably at least about 95% by weight, more preferably at least about 99% by weight of crystalline Form AG.

[0493] Also, certain embodiments provide compositions comprising 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, wherein at least 95% by weight, preferably at least 97% by weight, and more preferably at least 99% by weight of the 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide is Crystalline Form AG.

[0494] In a further embodiment, there is provided a pharmaceutical composition comprising crystalline Form AG of Compound (I) and at least one pharma- ceutically acceptable carrier and / or diluent.

[0495] In certain embodiments, the pharmaceutical composition comprises substantially pure crystalline Form AG of Compound (I), and at least one pharma- ceutically acceptable carrier and / or diluent.

[0496] In certain embodiments, crystalline Form AG of Compound (I) is combined with at least one pharma- ceutically acceptable carrier and / or diluent to provide at least one pharmaceutical composition.

[0497] In some embodiments, the pharmaceutical composition comprises crystalline Form AG of Compound (I) and other solid forms of Compound (I). The other solid forms may be, for example, other crystalline and / or amorphous solids of Compound (I).

[0498] Crystals may be produced by a variety of methods, such as, for example, crystallization or recrystallization from a suitable solvent, sublimation, crystal growth from the melt, change from another phase to the solid state, supercritical crystallization, and jet atomization. Techniques for crystallization or recrystallization of crystals from mixed solvents include, for example, evaporation of the solvent, cooling the temperature of the solvent mixture, seeding a supersaturated solvent mixture of molecules and / or salts with crystals, freeze-drying the solvent mixture, and adding an anti-solvent (counter-solvent) to the solvent mixture. High-throughput crystallization techniques can be used to produce crystals, including polycrystals.

[0499] Drug crystals (including polycrystals), methods for preparation, and characterization of drug crystals are reviewed in Solid-State Chemistry of Drugs, SR Byrn, RR Pfeiffer, and JG Stowell, 2nd Edition, SSCI, West Lafayette, Indiana (1999).

[0500] In solvent-based crystallization techniques, the choice of solvent or solvent mixture generally depends on one or more factors, such as the solubility of the compound, the crystallization method, and the vapor pressure of the solvent. Solvent combinations may also be used, for example, by dissolving a compound in a first solvent to obtain a solution, followed by the addition of an anti-solvent to reduce the solubility of the compound in the solution to form crystals. An anti-solvent is a solvent in which the compound has low solubility.

[0501] One method of forming crystals is to suspend and / or stir the compound in a suitable solvent to form a slurry, which may be heated to promote dissolution. As used herein, the term "slurry" refers to a saturated solution of the compound, which may also contain additional compounds to obtain a heterogeneous mixture of the compound and the solvent at a given temperature.

[0502] Seeds may be added to any mixture to be crystallized to promote crystallization. Seeding may be used to control the growth of a particular polymorph or the particle size distribution of the crystalline product. The calculated amount of seeds required will therefore vary depending on the size of the seeds used and the desired average size of the product particles, as described, for example, in "Programmed Cooling of Batch Crystallizers," JW Mullin and J. Nyvlt, Chemical Engineering Science, 1971,26, 369-377. In general, small size seeds are required to effectively control the growth of crystals in the mixture. Small size seeds may be produced by sieving, grinding, or micronizing larger crystals, or by microcrystallization of a solution. Care must be taken to ensure that the grinding or micronizing of the crystals does not cause the desired crystal form to change (i.e., to amorphous or another polymorphic form).

[0503] The cooled crystallization mixture may be vacuum filtered, and the isolated solids may be washed with a suitable solvent (e.g., the cooled recrystallization solvent) and dried by purging with nitrogen to obtain the desired crystalline form. The isolated solids may be analyzed by one or more suitable spectroscopic or analytical techniques (e.g., solid-state nuclear magnetic resonance, differential scanning calorimetry, X-ray powder diffraction, etc.) to assess the formation of the desired product crystalline form. The resulting crystalline form is generally obtained in an amount of about 70% by weight or more isolated yield, preferably 90% by weight or more isolated yield, based on the mass of the original compound used in the crystallization process. The product may be ground together or sieved to break down the product, if necessary.

[0504] The crystalline form may be produced directly from the reaction solvent of the final process of producing compound (I). For example, it may be produced by using a solvent or mixture of solvents from which compound (I) can be crystallized in the final process step. Alternatively, the crystalline form may be obtained by distillation or solvent addition. Suitable solvents for this purpose include, for example, the non-polar and polar solvents mentioned above, including protic polar solvents (e.g., alcohols) and aprotic polar solvents (e.g., ketones).

[0505] The presence of more than one polycrystal in a sample can be determined, for example, by powder X-ray diffraction (PXRD) or solid-state nuclear magnetic resonance spectroscopy (ssNMR). For example, the presence of extra peaks in a comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern can indicate the presence of more than one polycrystal in a sample. The simulated PXRD can be calculated from single crystal X-ray data. See Smith, DK, "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

[0506] The crystalline forms of Compound (I) described herein may be characterized using a variety of techniques whose operation is well known to those skilled in the art. The crystalline forms may be evaluated and identified using single crystal X-ray diffraction based on unit cell measurements of a single crystal at a certain analysis temperature. A detailed description of unit cells is provided in Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is incorporated herein by reference. Alternatively, the characteristic configuration of atoms in the crystal lattice may be evaluated according to the observed partial atomic configuration. Another technique for evaluating the crystal structure is powder X-ray diffraction analysis. In this analysis, the diffraction profile measured at the same analysis temperature is compared with a simulated profile representing the pure powder material, and the measurements of interest are evaluated at a range of 2θ values ​​(e.g., 2, 3, 4 or more).

[0507] Other methods may be used to characterize crystalline forms, including solid-state nuclear magnetic resonance (ssNMR), differential scanning calorimetry (DSC), thermography, and visual inspection of the crystalline or amorphous form. Two or more of these features may be combined to characterize the crystalline form of interest.

[0508] (usefulness) The crystalline forms of Compound (I) described herein can be used to isolate Compound (I) from other components at the completion of the synthesis process and / or to purify Compound (I) by one or a series of crystallization steps. The isolation and purification steps can be performed simultaneously or independently. Each crystalline form described herein can also be used to make other solid forms of Compound (I), such as amorphous Compound (I). In further embodiments, the amorphous Compound (I) is then used to form a dosage form for clinical use, such as a dosage form that includes a solid dispersion of amorphous Compound (I).

[0509] The crystalline forms of Compound (I) described herein may be used alone or in combination with other crystalline forms of Compound (I) (including other crystalline forms described herein) and / or may be formulated with one or more excipients or other pharma- ceutical active ingredients to form pharmaceutical compositions.

[0510] Working Example The present invention is further illustrated by the following examples which are preferred embodiments of the invention. All temperatures are in degrees Celsius (° C.) unless otherwise specified. These examples are illustrative rather than limiting, and it is understood that other embodiments may exist which do not depart from the spirit and scope of the invention.

[0511] For ease of description, the following abbreviations may be used herein: [Table 23]

[0512] Example 1: Preparation of Crystalline Form L of Compound (I) An equimolar amount of gentisic acid (32.9 mg; 0.2 mmol) was added to compound (I) (84.4 mg; 0.2 mmol) in acetonitrile (1.0 mL) to obtain a suspension, which was slurried at 75° C. for one day. After one day, a suspension consisting of birefringent particles was obtained. The suspension was filtered hot under positive pressure to obtain a solid. The solid constitutes crystalline form L.

[0513] Example 2: Preparation of Crystalline Form M of Compound (I) A suspension of compound (I) (84.4 mg; 0.2 mmol) in acetonitrile (1.0 mL) was allowed to stand at 75° C. Two molar equivalents of HBr (47 μL) were added to the suspension to obtain a solution. A solid immediately precipitated from the solution, forming a suspension. The suspension was filtered hot under positive pressure to obtain a solid. The solid constituted crystalline form M.

[0514] Example 3: Preparation of Crystalline Form N of Compound (I) Compound (I) (79.6 mg; 0.19 mmol) was suspended in water and approximately equimolar amount of nitric acid (15 μL; 0.25 mmol) was added to obtain a solution. The solution was purged with nitrogen and evaporated to obtain a solid. The solid constituted crystalline Form N.

[0515] Example 4: Preparation of Crystalline Form O of Compound (I) p-Toluenesulfonic acid (38.8 mg, 0.20 mmol) was dissolved in ethyl acetate (1 mL) and added to an approximately equimolar amount of compound (I) (74.1 mg, 0.17 mmol) to obtain a suspension. After slurrying overnight, a gel containing birefringent particles was formed. The clear supernatant was decanted and allowed to stand at room temperature for 10 days, after which a birefringent solid precipitated. This solid constitutes crystalline Form O.

[0516] Example 5: Preparation of Crystalline Form P of Compound (I) A suspension of Compound (I) (84.4 mg; 0.2 mmol) in acetonitrile (1.0 mL) was allowed to stand at 75° C. Two molar equivalents of HBr (47 μL) were added to the suspension to obtain a solution. A solid then quickly precipitated from the solution to form a suspension. The suspension was hot filtered under positive pressure. The filtrate was quickly cooled to room temperature to obtain a solid. The solid constituted crystalline Form P.

[0517] Example 6: Preparation of Crystalline Form Q of Compound (I) A portion of ethyl acetate (1 mL) was saturated with malonic acid at 60° C. The saturated solution was hot filtered onto a sample of compound (I) (70.9 mg; 0.17 mmol). The resulting suspension was slurried at 60° C. for 8 days to yield a suspension of birefringent particles. The suspension was hot filtered under positive pressure to yield a solid, which constitutes Crystalline Form Q.

[0518] Example 7: Preparation of Crystalline Form R of Compound (I) 1,2-ethanedisulfonic acid dihydrate (19.7 mg, 0.085 mmol) was dissolved in acetone at 50° C. This solution was added to 2 molar equivalents of Compound (I) (67.7 mg, 0.16 mmol) and the resulting suspension was slurried at 50° C. for 90 minutes, during which the suspension contained birefringent particles. The suspension was filtered hot under positive pressure to obtain a solid, which constitutes Crystalline Form R.

[0519] Example 8: Preparation of Crystalline Form S of Compound (I) In one experiment, compound (I) (88.7 mg, 0.21 mmol) was suspended in chloroform (0.75 mL), 2 molar equivalents of 2-hydroxyethanesulfonic acid (35 μL, 0.42 mmol) were added, and the resulting solution was stirred at room temperature for 1 week and then evaporated. The resulting gel was dried under vacuum and then suspended in acetone to give a suspension of birefringent particles. The suspension was slurried for 4 days and then filtered to isolate the solid, which constitutes crystalline Form S. Crystalline Form S was also isolated from acetonitrile and an equimolar amount of 2-hydroxyethanesulfonic acid. A suspension of Compound (I) (71.3 mg, 0.17 mmol) in acetonitrile (1 mL) was slurried at 70° C. for 30 minutes, after which an equimolar amount of 2-hydroxyethanesulfonic acid (16.4 μL, 0.17 mmol) was added to obtain a suspension. This suspension was slurried at 70° C. for 1 week, cooled to room temperature to give a solution, which was then evaporated. The resulting solid constitutes Crystalline Form S.

[0520] Example 9: Preparation of Crystalline Form T of Compound (I) A suspension of maleic acid (43.5 mg, 0.36 mmol) in chloroform:ethyl acetate (v / v=1:1, 1 mL) was added to 0.5 molar equivalents of Compound (I) (73.6 mg; 0.17 mmol) to obtain a suspension. The sample was slurried at room temperature for 2 weeks to obtain a suspension of birefringent particles. The suspension was filtered under positive pressure to obtain a solid. The solid constituted crystalline Form T.

[0521] Example 10: Preparation of Crystalline Form U of Compound (I) Compound (I) (73.7 mg; 0.17 mmol) was suspended in p-dioxane (1 mL) at 75° C. Approximately 2 molar equivalents of naphthalene-1,5-disulfonic acid (128.5 mg, 0.45 mmol) were added to the suspension at 75° C. to give a gel containing birefringent particles. The sample was slurried at ambient temperature for 6 days to give a gel containing non-birefringent particles. Toluene was added to the gel (2×1 mL) to give a suspension. The suspension was slurried at room temperature for 2 days and then filtered under positive pressure to give a solid. The solid constitutes Form U.

[0522] Example 11: Preparation of Crystalline Form V of Compound (I) Compound (I) (83.5 mg, 0.20 mmol) was suspended in water (1 mL) and allowed to stand at 80° C. Two molar equivalents of nitric acid (25 μL, 0.40 mmol) were added to the suspension, resulting in a solution containing a small amount of solid. The reaction was filtered while hot, cooled to room temperature, and concentrated to give a gel. Diisopropyl ether (1 mL) was added to give a suspension of birefringent microparticles. The suspension was slurried at room temperature for 2 days, and then filtered under positive pressure to give a solid. This solid constitutes Crystalline Form V.

[0523] Example 12: Preparation of Crystalline Form W of Compound (I) Compound (I) (70.1 mg, 0.16 mmol) and an approximately equimolar amount of benzenesulfonic acid (32.0 mg; 0.20 mmol) were combined and a portion of ethyl acetate (1 mL) was added to obtain a suspension. This suspension was slurried at 60° C. for one week to obtain a suspension of birefringent particles. The suspension was filtered under positive pressure to obtain a solid. This solid constitutes Crystalline Form W.

[0524] Example 13: Preparation of Crystalline Form X of Compound (I) Compound (I) (62.9 mg, 0.15 mmol) and an approximately equimolar amount of naphthalene-1,5-disulfonic acid (56.1 mg, 0.19 mmol) were suspended in acetone (1 mL) and slurried at 50° C. for one week to obtain a suspension of birefringent particles. This suspension was filtered under positive pressure to obtain a solid. This solid constitutes Crystalline Form X.

[0525] Example 14: Preparation of Crystalline Form Y of Compound (I) Compound (I) (67.1 mg, 0.16 mmol) was suspended in 2-methyltetrahydrofuran (1 mL) and 1.5 molar ethanesulfonic acid (20.6 μL) was added. A solid remained after the addition of the acid and the sample was stirred at 70° C. for 1 week to give a gel. Methyl tert-butyl ether (1 mL) was added and the sample was triturated at room temperature for 2 days to give a suspension. The suspension was filtered under positive pressure to give a solid. The solid constituted crystalline Form Y.

[0526] Example 15: Preparation of Crystalline Form Z of Compound (I) Compound (I) (360 mg) was dissolved in tetrahydrofuran:water (v / v=95:5, 24 mL) at ambient temperature. A solid was isolated by adding 96% sulfuric acid (47 μL) and quickly evaporating. This isolated solid (90 mg) was suspended in ethanol:water (v / v=1:2, 1 mL) at 60° C. and stirred overnight. The solid suspended in the slurry constitutes crystalline Form Z.

[0527] Example 16: Preparation of Crystalline Form AA of Compound (I) Compound (I) (360 mg) was dissolved in tetrahydrofuran:water (v / v=95:5, 24 mL) at ambient temperature and 96% sulfuric acid (47 μL) was added. A solid was isolated by rapid evaporation. The isolated solid (90 mg) was suspended in butyl acetate (1 mL) at 60° C. and stirred overnight. The suspension was filtered and the filtered solid was dried in a vacuum oven at 50° C. overnight. The dried solid constituted crystalline Form AA.

[0528] Example 17: Preparation of Crystalline Form AB of Compound (I) Compound (I) (360 mg) was dissolved in tetrahydrofuran:water (v / v=95:5, 24 mL) at ambient temperature. A solid was isolated by adding 96% sulfuric acid (47 μL) and quickly evaporating. The isolated solid (90 mg) was suspended in IPAc (1 mL) at 60° C. and stirred overnight. The suspension was filtered and the filtered solid was dried in a vacuum oven at 50° C. overnight. The dried solid constituted crystalline Form AB.

[0529] Example 18: Preparation of Crystalline Form AC of Compound (I) Compound (I) (360 mg) was dissolved in tetrahydrofuran:water (v / v=95:5, 24 mL) at ambient temperature. A solid was isolated by adding 37% hydrochloric acid (142 μL) and quickly evaporating. This isolated solid (90 mg) was stirred in ethanol:water (v / v=1:2, 1 mL) at 60° C. and stirred overnight. The solid suspended in the slurry constitutes crystalline Form AC.

[0530] Example 19: Preparation of Crystalline Form AD of Compound (I) Compound (I) (360 mg) was dissolved in tetrahydrofuran:water (v / v=95:5, 24 mL) at ambient temperature. A solid was isolated by adding methanesulfonic acid (55 μL) and quickly evaporating. The isolated solid (90 mg) was suspended in IPAc (1 mL) at 60° C. and stirred overnight. The suspension was filtered and the filtered solid was dried in a vacuum oven at 50° C. overnight. The dried solid constituted crystalline Form AD.

[0531] Example 20: Preparation of Crystalline Form AE of Compound (I) Compound (I) (360 mg) was dissolved in tetrahydrofuran:water (v / v=95:5, 24 mL) at ambient temperature. A solid was isolated by adding 85% phosphoric acid (58 μL) and quickly evaporating. The isolated solid (90 mg) was suspended in isopropyl acetate (1 mL) at 60° C. and stirred overnight. The suspension was filtered and the filtered solid was dried in a vacuum oven at 50° C. overnight. The dried solid constitutes crystalline Form AE. Alternatively, the solid isolated by flash evaporation from the first method above (90 mg) was suspended in butyl acetate (1 mL) at 60° C. and stirred overnight. The suspension was filtered and the filtered solid was dried in a vacuum oven overnight at 50° C. The dried solid constitutes crystalline Form AE.

[0532] Example 21: Preparation of Crystalline Form AF of Compound (I) Compound (I) was dissolved in ethanol:water (v:v=90:10) at 70° C. to a concentration of 19 mg / mL. The solution was hot filtered into a new vial and cooled to 2-8° C. The precipitated solid constituted crystalline Form AF. Crystalline Form AF is also produced by several different methods. In one method, the solid obtained by suspending Compound (I) (Crystalline Form B) in ethanol:water (v:v=90:10) at 2-8°C for 14 days constitutes Crystalline Form AF. Alternatively, the solid obtained by suspending Compound (I) (Crystalline Form B) in ethanol:water (v:v=80:20) at 2-8°C and room temperature for 14 days constitutes Crystalline Form AF. In yet another method, the solid obtained by suspending Compound (I) (Crystalline Form B) in ethanol:water (v:v=64:36) at room temperature for 14 days constitutes Crystalline Form AF.

[0533] Example 22: Preparation of Crystalline Form AG of Compound (I) Compound (I) (Crystalline Form B) is suspended in acetic acid at room temperature for 14 days, and the resulting solid constitutes Crystalline Form AG. Alternatively, Compound (I) was dissolved in acetic acid at 70° C. to a concentration of 42 mg / mL. The solution was filtered while hot, and the filtered solution was cooled to room temperature at a rate of 20° C. / hr. The resulting clear solution was further cooled to 2-8° C., then cooled to −15 to −25° C. The solution was brought to room temperature and ethyl acetate was added to give a final acetic acid:ethyl acetate ratio of 1:3 (v:v). A solid was observed within 10 minutes of the addition of ethyl acetate. The solid constituted crystalline form AG.

[0534] 6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 ) Synthesis of pyridazine-3-carboxamide Step 1: Preparation of Compound 2 [ka] Toluene (0.26 kg), sulfolane (3.4 kg), compound 1 (1.0 kg), and POCl3 (2.7 kg) were added to a glass-lined reactor and the crude was cooled to 0° C. Triethylamine (0.89 kg) was added and the crude mixture was heated at 65° C. The reaction was aged until complete and the reaction was cooled to 5° C. Water (7.5 kg) was added to a separate vessel and cooled to 5°C. The reactants were slowly added to the water to maintain the internal temperature below 5°C. Water (0.5 kg) was added to rinse the reactor and the wash was decanted. The mixture was stirred at 5°C for 3 hours and then extracted three times with MTBE (3x4.5 kg). The combined organic layers were washed sequentially with pH 7 buffer solution (5.0 L / kg, 15 wt% KH2PO4 / K2HPO4) and water (2.5 kg). The resulting crude was vacuum distilled to a total volume of approximately 3 L / kg. ACN (2x6.3 kg) was added and subsequently distilled again to return to ~3 L / kg. The resulting crude was cooled to 20°C to give compound 2 as a 30-36 wt% solution (90-95% yield).

[0535] Step 2: Preparation of compound 3 [ka] ACN (2.7 kg), lithium bromide (1.18 kg) and water (0.65 kg) were charged to a glass-lined reactor at 25° C. The crude solution of compound 2 (limiting reagent) prepared above was added followed by DIPEA (1.82 kg). The resulting slurry was stirred at 25° C. until the reaction was complete and the product was isolated by filtration. The resulting crude solid was washed with ACN (1.6 kg) and the cake was dried under vacuum at 45° C. Compound 3 was isolated (AP 98 and 83% yield).

[0536] Step 3: Preparation of compound 8 TIFF2024529763000027.tif51136Water (6.0 kg, 6.0 L / kg) and compound 7 (1.0 kg) were placed in a glass-lined reactor at 25° C., and zinc acetate anhydrous (1.08 kg, 1.0 equiv.) was added, followed by compound 3 (1.28 kg, 1.20 equiv.). The reactor lines were rinsed with 2-propanol (0.79 kg, 1.0 L / kg) and water (1.50 kg, 1.50 L / kg). The resulting homogeneous solution was heated at 65° C. and aged until the reaction was complete. Water (7.0 kg, 7.0 L / kg) was added, and the resulting crude mixture was cooled to 20° C. and aged for 30 minutes. The product was isolated by filtration. The resulting crude solid was washed successively with water (6.0 kg, 6.0 L / kg), water (6.0 kg, 6.0 L / kg), THF (5.3 kg, 6.0 L / kg) and THF (5.3 kg, 6.0 L / kg). The cake was dried under vacuum at 70° C. and compound 8 was isolated (AP 98 and yield 94%).

[0537] Step 4: Preparation of compound 9 [ka] Another glass-lined reactor was purged with nitrogen. Toluene (0.87 kg, 1.0 L / kg) and MeCN (0.79 kg, 1.0 L / kg) were added, followed by (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (Josiphos SL-009-01) (14.1 g, 1.0 mol%) and palladium acetate (2.9 g, 0.5 mol%), and the reactor lines were rinsed with toluene (0.43 kg, 0.5 L / kg). This pre-prepared catalyst solution was stored under nitrogen until use. At 20°C, toluene (3.46 kg, 4.0 L / kg) and ACN (1.57 kg, 2.0 L / kg) were added to a nitrogen-purged glass-lined reactor. Compound 8 (1.00 kg) was added, followed by DBU (0.39 kg, 1.00 eq.), and the reactor lines were rinsed with toluene (0.43 kg, 0.5 L / kg). Compound 10 (0.54 kg, 2.5 eq.) and K2CO3 (325 mesh, 0.70 kg, 2.0 eq.) were added to the reaction mixture, followed by toluene (1.30 kg, 1.5 L / kg) and ACN (0.79 kg, 1.0 L / kg). The previously prepared catalyst solution was transferred to the reaction mixture, which was then heated to 75°C and stirred until the reaction was complete. The reaction crude was cooled to 20° C. and aqueous acetic acid (50% by volume, 4.0 kg, 4.0 L / kg) was added slowly over 1 hour. Glacial acetic acid (10.5 kg, 10.0 L / kg) was then added and the resulting homogenous solution was washed twice with heptane (2×3.42 kg, 2×5.0 L / kg). The lower aqueous layer was collected and transferred to a clean reactor. Water (5.0 kg, 5.0 L / kg) was added followed by compound 9 seeds (0.01 kg, 1.0 wt%). The slurry was aged at 20° C. for 2 hours. Additional water (2.0 kg, 2.0 L / kg) was added and the slurry was aged for an additional 6 hours. The product was isolated by filtration and the resulting crude cake was washed with aqueous ACN (50% by volume, 4.5 kg, 5.0 L / kg) followed by ACN (3.9 kg, 5.0 L / kg). The cake was dried under vacuum at 65° C. and compound 9 was isolated (AP 98.5 and yield 84%).

[0538] Step 5: Preparation of Compound (I) [ka] NMP (2.06 kg, 2.0 L / kg) and ACN (0.78 kg, 1.0 L / kg) were placed in a glass-lined reactor and stirred at 20 °C. N-methylimidazole (0.13 kg, 0.7 eq), compound 13 (0.17 kg, 1.2 eq), and compound 9 (1.00 kg) were added to the reaction mixture. The mixture was heated at 65 °C and aged until homogeneous. HOBt (20% hydrate, 0.17 kg, 0.5 eq) was then added to the reaction mixture, followed by EDC·HCl (0.54 kg, 1.4 eq). The reaction vessel was rinsed with ACN (0.78 kg, 1.0 L / kg), and the resulting mixture was then aged at 65 °C until the reaction was complete. Water (1.0 kg, 1 L / kg) was added to quench the reaction, and then it was diluted with ACN (3.0 kg, 3 L / kg). The reaction mixture was aged at 65° C. for 1 hour, then cooled to 0° C. and aged at 0° C. for an additional 12 hours. The product was isolated by filtration and the wet cake was washed with water:ACN (2:1, 2.8 kg, 3 L / kg) followed by ACN (2.4 kg, 3 L / kg). After drying in vacuum at 65° C., compound (I) was isolated (purity >99.5%, yield 91%). NMP (6.2 kg, 6.0 L / kg) and compound (I) (1.0 kg) were charged to a glass-lined reactor and the batch was heated at 70° C. to obtain a solution. This was then transferred to a clean reactor at 70° C. by polish filtration. 2-propanol (2.4 kg, 3 L / kg) was added followed by compound I seeds (0.005 kg, 0.005 kg / kg). After aging for 1 hour, 2-propanol (4.8 kg, 6 L / kg) was added over 2 hours (3 L / kg / hr). The slurry was aged at 70° C. for 1 hour, cooled slowly to 0° C., and aged at 0° C. for an additional 12 hours. The product was isolated by filtration and the wet cake was washed with 2-propanol (2×3.1 kg, 2×4 L / kg) before being dried under vacuum at 65° C. to isolate compound (I) (purity >99.9%, yield 83%).

[0539] Preparation of compound 7 Step 1: Preparation of N-methyl-N-formylhydrazine TIFF2024529763000030.tif18102 Methanol (1.6 kg / kg, 2.0 L / kg) and methylhydrazine (1 kg) were added to a glass-lined reactor at 0°C, followed by dropwise addition of methyl formate (0.57 kg / kg, 1.1 equiv.). The crude material was warmed to 20°C and aged for an additional 6 h. The crude material was vacuum distilled to a total volume of approximately 0.5 L / kg. Distillation was repeated five times with 2-MeTHF to azeotrope and dry (5x3.6 kg / kg). The crude material was cooled to 20°C, and N-methyl-N-formylhydrazine was isolated as an 89-90 wt% solution (yield 89-91%).

[0540] Step 2: Preparation of compound 5 [ka] Potassium tert-butoxide (1.5 kg / kg, 2.4 equiv.) and THF (12.2 kg / kg) were added to a glass-lined reactor at 0° C., and a mixture of compound 4 (1.0 kg), N-methyl-N-formylhydrazine (1.0 kg / kg, 2.30 equiv.) and THF (5.3 kg / kg, 6.0 L / kg) was added slowly. The reactor lines were rinsed with THF (0.5 kg / kg) and the reaction crude was aged at 0° C. until the reaction was complete. Water (5.0 kg / kg) was added and the resulting mixture was aged at 0° C. for 30 minutes, heated to 40° C. and aged for an additional 30 minutes. The layers were separated and the aqueous layer was discarded. The organic layer was washed with brine (15 wt %, 5.7 kg / kg) and then vacuum distilled to a total volume of approximately 5 L / kg. Distillation was repeated four times with ethyl acetate to dryness (4x10 L / kg). The resulting crude was cooled to 20°C, sulfuric acid (0.66 kg / kg, 1.10 equiv.) was added, and the resulting slurry was stirred for 2-3 h. The product was isolated by filtration, and the cake was washed successively with ethyl acetate (2x6.5 L / kg) and heptane (8 L / kg). After drying in vacuum at 45°C, compound 5 was isolated (AP 99 and 83% yield).

[0541] Step 3: Preparation of compound 6 [ka] Concentrated sulfuric acid (4.5 kg / kg) and compound 5 (1.0 kg) were added to a glass-lined reactor at 0-5° C., and nitric acid (68 wt%, 0.35 kg / kg, 1.2 equiv.) was added dropwise. The mixture was stirred at 0-5° C. until the reaction was complete. In a separate vessel, water (12 kg / kg) and methanol (6.5 kg / kg, 8.3 L / kg) were mixed well at 20°C. The nitrated crude was slowly transferred to the methanol-water mixture and the reactor lines were rinsed with methanol (0.5 kg / kg). The resulting crude was heated at 40-45°C and aqueous ammonium hydroxide (25 wt%, 7.4 kg / kg) was slowly added. The resulting slurry was cooled to 20°C and stirred for 3 hours. The product was isolated by filtration and the cake was washed with water (2x6 L / kg) and dried under vacuum at 45°C to isolate compound 6 (AP 99, 95% yield).

[0542] Step 4: Preparation of compound 7 [ka] Methanol (8.0 kg / kg) and compound 6 (1.0 kg) were added to a nitrogen-purged high-pressure reactor. Oxygen was carefully removed and sodium bicarbonate (0.6 kg / kg, 2.0 equiv.) and 10% Pd / C (50% water-wet, 0.02 kg / kg) were added. The reactor was pressurized with hydrogen (41-46 psi) and the reaction mixture was aged at 20°C for 6 hours. It was then heated to 45°C and aged until the reaction was complete. The reactor was purged with nitrogen and the reaction crude was filtered to remove the Pd / C. Methanol (5 kg / kg) was added to aid in the filtration. The filtrate was combined and vacuum distilled to a total volume of approximately 2.5 L / kg. Water (10 kg / kg) was added and the resulting crude was vacuum distilled to a total volume of approximately 2.5 L / kg. The crude was heated at 70° C., brine (25 wt%, 9.0 kg / kg) was added, and the resulting crude was stirred at 70° C. for 6 h. After cooling to 0° C., the crude was aged for an additional 6 h. The product was isolated by filtration and the cake was washed with brine (pre-cooled to 0° C., 25 wt%, 2.0 kg / kg). After drying in vacuum at 45° C., compound 7 was isolated (AP 99, 88% yield).

[0543] Preparation of compound 13 Step 1: Preparation of Compound 11 and Compound 12 [ka] A nitrogen-purged glass-lined reactor was charged with water (16.3 L / kg) and sodium hydroxide (3.3 kg, 3.0 equiv.) and the mixture was aged until the sodium hydroxide was completely dissolved. The crude was cooled to 0° C. and d4-methanol (1.0 kg) and THF (4.5 L / kg) were added. A solution of TsCl (6.3 kg, 1.2 equiv.) in THF (6.3 kg, 7.1 L / kg) was added over 2 hours. The crude was stirred at 0° C. until the reaction was complete. The batch was warmed to 20° C. and the layers were separated. The combined organic layers were diluted with MTBE (4.0 kg, 5.4 L / kg) and washed twice with brine (25 wt %, 4.0 kg, followed by 12 kg). The organic layers were vacuum distilled to a total volume of approximately 10 L / kg. Two distillations were performed with ACN to azeotrope dryness (2x10 L / kg). The resulting crude was cooled to 20° C. and ACN (10.0 kg, 12.8 L / kg) and NaN(CHO)2 (3.3 kg, 1.2 equiv.) were added. The crude was heated at 65° C. and stirred until the reaction was complete. After cooling to 5° C., the mixture was filtered and the crude cake was washed twice with ACN (2×2.5 kg, 2×3.2 L / kg). The combined filtrate was distilled under reduced pressure to a total volume of approximately 3 L / kg. The resulting crude was cooled to 20° C. and compound 12 was isolated as an oil of 80-85 wt% (60-70% yield).

[0544] Step 2: Preparation of compound 13 [ka] Compound 12 (1.0 kg) and methanol (3.9 kg, 5.0 L / kg) were added to a glass-lined reactor at 20°C, followed by a solution of HCl / IPA (5-6 normal, 4.5 kg, 1.5 equiv). The mixture was heated at 50°C and stirred until the reaction was complete. THF (10 kg, 11.2 L / kg) was added slowly and the resulting crude was cooled to 0°C over 2 hours to give a slurry. The product was isolated by filtration and the cake was washed with THF (3.7 kg, 4.1 L / kg). After drying in vacuum at 45°C, compound 13 was isolated (80% yield).

[0545] Recrystallization of Compound 13 (Optional): Methanol (5.6 kg, 8.3 L / kg) and 13 (1.0 kg) were placed in a glass-lined reactor, DBU (0.1 kg) was added slowly, and the crude was stirred for 1 h. THF (12.4 kg, 13.9 L / kg) was added slowly, and the resulting slurry was aged for 2 h. The product was isolated by filtration, and the cake was washed with THF (2.6 kg, 2.9 L / kg). 13 was isolated after drying in vacuum at 45° C. (60% yield, first crop). The mother liquor was distilled under reduced pressure to a total volume of approximately 1 L / kg. Two repeated distillations with methanol (2×2.8 kg, 2×3.6 L / kg) were performed to concentrate the solution back to ∼1 L / kg. The resulting crude was cooled to 20° C. THF (4.8 kg, 5.4 L / kg) was added, and the resulting slurry was aged for 2 h. The product was isolated by filtration, the cake was washed with THF (1.0 kg) and dried in vacuum at 45° C. to isolate compound 13 (25% yield, 2nd crop).

[0546] 1. Single Crystal X-ray Measurements Crystal Z : Single crystal X-ray data for crystal Z were collected using a Kappa diffractometer (Bruker) equipped with an APEX II CCD detector and a MICROSTAR (a microfocus rotating anode X-ray generator with monochromatic CuKα radiation). The single crystal was at room temperature during data collection. Indexing and processing of the measured intensity data was performed with the APEX2 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA). The final unit cell parameters were determined using the complete data set. The structure was solved by direct methods and refined by full-matrix least-squares fitting using the SHELXTL software package (GM Sheldrick, SHELXTL v6.14, Bruker AXS, Madison, WI USA.). The structure was refined using the Σw(|Fo|-|Fc|) 2where w is an appropriate weighting factor based on the observed intensity error, Fo is the measured scattering-based structure factor, and Fc is the theoretical scattering-based structure factor. The agreement between the refined crystal structure model and the experimental X-ray diffraction data is measured using the R-factor = Σ||Fo|-|Fc|| / Σ|Fo| and wR = [Σw(|Fo|-|Fc|) 2 / Σw|Fo|] 1 / 2 The lattice constants are evaluated using the σ-values. Difference Fourier maps were performed at all stages of the refinement. All non-hydrogen atoms were refined with anisotropic thermal displacement parameters. Hydrogen atoms were introduced with isotropic temperature factors using theoretical geometry and incorporated with fixed parameters in the structure factor calculations.

[0547] Crystal AC : Single-crystal X-ray data for crystal AC were collected using an X8-Proteum diffractometer (Bruker) equipped with an APEX II CCD detector and a MICROSTAR (a microfocus rotating anode X-ray generator with monochromatic CuKα radiation). The single crystal was at room temperature during data collection. Indexing and processing of the measured intensity data was performed with the APEX2 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA). The final unit cell parameters were determined using the complete data set. The structure was solved by direct methods and refined by full-matrix least-squares fitting using the SHELXTL software package (GM Sheldrick, SHELXTL v6.14, Bruker AXS, Madison, WI USA.). The structure was refined using the Σw(|Fo|-|Fc|) 2 where w is an appropriate weighting factor based on the observed intensity error, Fo is the measured scattering-based structure factor, and Fc is the theoretical scattering-based structure factor. The agreement between the refined crystal structure model and the experimental X-ray diffraction data is measured using the R-factor = Σ||Fo|-|Fc|| / Σ|Fo| and wR = [Σw(|Fo|-|Fc|) 2 / Σw|Fo|] 1 / 2 The lattice constants are evaluated using the σ-values. Difference Fourier maps were performed at all stages of the refinement. All non-hydrogen atoms were refined with anisotropic thermal displacement parameters. Hydrogen atoms were introduced with isotropic temperature factors using theoretical geometry and incorporated with fixed parameters in the structure factor calculations.

[0548] 2. Powder X-ray Diffraction PXRD patterns of selected crystals L, M, N, O, P, Q, R, U, V, and W were collected on an X'Pert PRO MPD diffractometer (PANalytical) (X-ray source: Cu long anode, fine focus, Optix). An elliptically tilted multilayer mirror was used to focus the CuKα X-rays through the sample onto the detector. Prior to analysis, the Si 111 peak position was confirmed on a silicon sample (NIST SRM 640e). The samples were sandwiched between 3 μm thick films and analyzed in transmission. A beam stopper and scattering slit were used to minimize air background. Soller slits were used on the incident and diffracted beam sides to minimize broad peak widths due to axial divergence. Diffraction patterns were collected using a high-speed semiconductor array detector (X'Celerator) located 240 mm away from the sample and data collection software (v.5.5).

[0549] PXRD patterns of crystals S, T, X and Y were collected on an Empyrean diffractometer (PANalytical) (X-ray source: Cu long anode, fine focus). An elliptically tilted multilayer mirror was used to focus the CuKα X-rays through the sample onto the detector. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to confirm that the Si 111 peak position matched the position confirmed by NIST. The samples were sandwiched between 3 μm thick films and analyzed in transmission. A beam stopper, scattering slits and anti-scatter knife edges were used to minimize air background. Soller slits were used on the incident and diffracted beam sides to minimize broad peak widths due to axial divergence. Diffraction patterns were collected using a high-speed semiconductor array detector (X'Celerator) located 240 mm away from the sample and data collection software (v.5.5).

[0550] PXRD data for Forms Z, AA, AB, AC, AD, and AE were obtained using a Bruker C2 GADDS. Radiation was CuKα (40 KV, 40 mA). The sample to detector distance was 15 cm. Samples were placed in sealed glass capillaries (diameter ≦1 mm). The capillaries were rotated during data collection. Data were collected from about 2≦2θ≦32° with sample exposure times of at least 1000 seconds. The resulting two-dimensional diffraction arcs were integrated to generate conventional one-dimensional PXRD patterns ranging from approximately 2 to 32 degrees 2θ with 0.05 degree 2θ steps.

[0551] 3. Differential Scanning Calorimetry Differential scanning calorimetry (DSC) experiments on crystalline forms AA, AB, and AE were performed using a Q1000 model (TA Instrument). The samples (approximately 1-10 mg) were weighed in aluminum pans and the weight was accurately measured to the hundredth of a milligram before the samples were transferred to the DSC. The instrument was purged with nitrogen gas at 50 mL / min. Data were collected between room temperature and 300°C at a heating rate of 10°C / min. DSC plots were made with the endothermic peak pointing downwards.

[0552] 4.Thermogravimetric analysis (TGA) Thermogravimetric analysis (TGA) experiments on crystalline Form AB were performed using a Q500 model (TA Instrument). The sample (approximately 10-30 mg) was placed in a pre-weighed platinum pan. The weight of the sample was accurately measured by the instrument and recorded to the nearest thousandth of a milligram. The furnace was purged with nitrogen gas at 100 mL / min. Data was collected between room temperature and 300°C at a heating rate of 10°C / min.

[0553] 5. Simultaneous thermogravimetric and differential thermal measurement (TGA-DSC) DSC / TGA analysis of crystalline forms L, M, N, R, S and W was carried out using a thermal analysis system TGA / DSC3+ (Mettler Toledo). Temperature calibration was performed using calcium oxalate, indium, tin and zinc. The samples were placed in an aluminum pan. The samples were covered with a lid, pierced and then placed in a thermogravimetric furnace. The furnace was heated under nitrogen with a flow rate of 50 mL / min. The method involves heating from room temperature to 350°C at a heating rate of 10°C / min.

Claims

1. 6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 ) Crystalline form R of pyridazine-3-carboxamide.

2. At least one of the following: (i) a powder X-ray diffraction (PXRD) pattern comprising two or more 2θ values ​​(°) (CuKα) selected from 9.5±0.2, 10.0±0.2, 16.4±0.2, 17.2±0.2, 22.0±0.2, and 22.8±0.2, wherein the PXRD pattern is measured at room temperature; (ii) the observed powder X-ray diffraction (PXRD) pattern is substantially as shown in Figure 10, wherein the PXRD pattern is measured at room temperature; (iii) a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 11 (bottom); (iv) exhibiting a weight loss of less than about 1.0% in a thermogravimetric analysis (TGA) thermogram when heated from about room temperature to about 200°C; (v) Thermogravimetric analysis (TGA) thermograms substantially as shown in Figure 11 (top). The crystalline substance according to claim 1, characterized in that

3. 2. The crystalline form of claim 1, characterized in that the powder X-ray diffraction (PXRD) pattern comprises three or more 2θ values ​​(°) (CuKα) selected from 9.5±0.2, 10.0±0.2, 16.4±0.2, 17.2±0.2, 22.0±0.2, and 22.8±0.2, wherein the PXRD pattern is measured at room temperature.

4. 2. The crystalline form of claim 1, characterized in that the powder X-ray diffraction (PXRD) pattern comprises 4 or more 2θ values ​​(°) (CuKα) selected from 9.5±0.2, 10.0±0.2, 16.4±0.2, 17.2±0.2, 22.0±0.2, and 22.8±0.2, wherein the PXRD pattern is measured at room temperature.

5. 2. The crystalline form of claim 1, characterized in that the powder X-ray diffraction (PXRD) pattern comprises 5 or more 2θ values ​​(°) (CuKα) selected from 9.5±0.2, 10.0±0.2, 16.4±0.2, 17.2±0.2, 22.0±0.2, and 22.8±0.2, wherein the PXRD pattern is measured at room temperature.

6. 2. The crystalline form of claim 1, wherein the powder X-ray diffraction (PXRD) pattern of the crystalline form measured at room temperature comprises 2θ values ​​(°) (CuKα) of 9.5±0.2 and 10.0±0.

2.

7. 7. The crystalline form according to claim 6, wherein the PXRD pattern further comprises one or more 2θ values ​​(°) (CuKα) selected from 16.4±0.2, 17.2±0.2, 22.0±0.2, and 22.8±0.

2.

8. 2. The crystalline form of claim 1, wherein the powder X-ray diffraction (PXRD) pattern of the crystalline form measured at room temperature comprises 2θ values ​​(°) (CuKα) of 9.5±0.2, 10.0±0.2, and 16.4±0.

2.

9. 2. The crystalline form of claim 1, wherein the powder X-ray diffraction (PXRD) pattern of the crystalline form measured at room temperature comprises 2θ values ​​(°) (CuKα) of 9.5±0.2, 10.0±0.2, 16.4±0.2, and 17.2±0.

2.

10. 2. The crystalline form of claim 1, wherein the powder X-ray diffraction (PXRD) pattern of the crystalline form measured at room temperature comprises 2θ values ​​(°) (CuKα) of 9.5±0.2, 10.0±0.2, 16.4±0.2, 17.2±0.2, and 22.0±0.

2.

11. 2. The crystalline form of claim 1, wherein the powder X-ray diffraction (PXRD) pattern of the crystalline form measured at room temperature comprises 2θ values ​​(°) (CuKα) of 9.5±0.2, 10.0±0.2, 16.4±0.2, 17.2±0.2, 22.0±0.2, and 22.8±0.

2.

12. 10. The crystalline form of claim 1, characterized in that (i) it has a powder X-ray diffraction (PXRD) pattern comprising 2θ values ​​(°) (CuKα) of 9.5±0.2 and 10.0±0.2, wherein the PXRD pattern is measured at room temperature; and (ii) it has a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 11 (bottom).

13. 6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 ) pyridazine-3-carboxamide, wherein at least 90% by weight of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 13. A composition wherein the pyridazine-3-carboxamide is crystalline Form R according to any one of claims 1 to 12.

14. A pharmaceutical composition comprising Crystalline Form R according to any one of claims 1 to 12.

15. below: (a) Prepare a solution by dissolving 1,2-ethanedisulfonic acid dihydrate in acetone at 50°C; (b) Add the above solution to 2 molar equivalents of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 ) pyridazine-3-carboxamide and form a suspension; (c) slurried the above suspension at 50°C for 90 minutes; and (d) The suspension is filtered hot under positive pressure to give 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 ) Obtain a solid containing crystalline form R of pyridazine-3-carboxamide A method for producing the crystalline body according to any one of claims 1 to 12, characterized by the steps of:

16. Amorphous 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d 3 13.) Use of crystalline form R according to any one of claims 1 to 12 in a method for preparing pyridazine-3-carboxamide.

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